151
Brain Research Reviews, 16 (1991) 151-169 @ 1991 Elsevier science Pubhshers B.V. Ah rights reserved. 01~~173~~3.~ ADONIS 01~1~9~~1~ BRESR 90128
Taurine: retinal function John B. Lombardini ~e~~~
of Pharmacology and ~~h~~olo~
d Vimal Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430 (U.S.A.) (Accepted 9 April 1991)
Key wor&: Taurine; Retinal function; Uptake system; Binding protein; Electroretinogram; Taurine deficiency; Retinal degeneration; Regulator of ionic transport; Inhibitor of protein phosphorylation
CONTENTS 1. Jntroduction
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151
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152
2. Taurine leveh
3. Synthetic enzymes
153
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4. Taurine binding proteins 5. Taurine uptake systems
.........................................................................................................................................
154
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6. Release mechanisms for tam-me ............................................................................................................................... 7. Effects of taurine on the electroretinogram
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9. Retinal degeneration
in animal models and humans due to taurine deficiency
154 155
................................................................................................................
8. Retinitis pigmentosa
153
156
..................................................................
156
10. Possible functions of taurine .................................................................................................................................... ....................................................................................................................... 10.1. Rote&ion of the photoreceptor 10.2. Regulation of CaZf transport .......................................................................................................................... ..................................................................................................................... 10.3. Regulation of signal infusion
157 157 158 162
11. summary
162
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Acknowledgements References
162
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1. JNTRODUCMON
Taurine (2-~~th~esu~o~c acid) is a /krnino sulfonic acid that is present in milhmolar inundations in the animal kingdom but usually reported to be absent in the plant kingdoms” except for a few references to its presence in fungi3’ and pollenI&. However, Lahdesmlki observed millimolar concentrations of taurine in green leaves, seeds, fruit, and tubers of various plant species94. The initial discovery249and isolationN of taurine in 1827 and 1838, respectively, occurred in ox bile, and thus the derivation of the name from Taurus the Bull. Taurine is Correspondence: J.B. Lombardini, U.S.A. Fax: (1) (806) 743-2744.
Department
of ~~a~io~,
163
present in high concentrations in all animal tissues but it is in mammalian systems that the study of taurine generates perhaps its greatest interest due to its wide spectrum of biological activities in various tissues. The many possible functions of taurine include the following gamut: (a) ne~otr~s~tter (or neurom~ulator) in the CNS”; (b) stabilizer of biological membranes in many tissues” which affects cardiovascular functionsss’218and protects lymphoblastoid cells19*and spermatozoa6 against loss of activity; (c) protector of rod outer segments (ROSS) from exposure to toxic levels of light and chemicals165* t81; (d) modulator of calcium binding and fluxes75,133,169; Texas Tech University Health sciences Center,
Lubbock, TX 79430,
152 and (e) inhibitor of protein phospho~lation10~110,1’3~~23~ 129
The various studies on taurine reveal a major problem (or perhaps strength) due to the fact that more than one animal species has been investigated with respect to the possible functions of taurine. Many properties of taurine differ among various animal models which have been studied, including man. For example, in terms of taurine synthesis the adult rat is clearly capable of synthesizing su~~ent quantities of taurine to maintain total body levels73*238while the cat, monkey, and man must depend upon an exogenous source of taurine, i.e. the diet47,48,55,87,239,243. While this review is restricted to taurine and the retina, it still suffers limitations in formulating a role for taurine because of the difficulty in summarizing investigations which utilized many different animal species. Unfortunately, from individual data, one could devise a composite role for taurine in the retina which does not apply specificically to any particular species. In 1968 the first ~mprehensive review of taurine was published by Jacobsen and Smithss and since 1975 a series of international symposia have been held to discuss the biochemistry, physiology and pharmacology of taurine. Interest in the function of taurine over the last two decades has been considerable as suggested by the numerous review articles and monographs devoted to this compound 14,29,30,66,67,69,71,74,79,91,161.165,185,210,219,239.265 2. TAURINE LEVELS
Several lines of evidence suggest that taurine has a role in retinal function. The retina contains an extremely high amount of taurine and in some animal species the taurine levels in the retina are the highest of any tissue26* 33,~,50,51,60,83,89.141,143,177,237,261,269
-l-wo
nota,,je
excep_
tions of tissues with higher taurine levels are the neurohypophysis and pineal gland of the rat35. In the rat retina, taurine is the most abundant free amino acid comprising more than 50% of the total amino acid Depending upon the species the taurine pool 6o,143*177. content ranges from 10 pmol/g wet wt. in the frog retina to 50 and 52 pmol/g wet wt. in the rat and rabit retina with an intermediate value of 24 pmol/g wet wt. for the human retinaZ1. Within the retina taurine appears to be unevenly distributed and is concentrated in the photorereaching levels as high as 79 mM ceptor layerS4,150*“63*260 in the rat260V261. Immunocytochemical techniques have also been utilized to localize taurine in the rat, cat and guinea pig retina’@‘@‘. High levels of immunostaining reflecting the presence of taurine were observed in photoreceptor inner segments and synaptic terminals. Also amacrine and
bipolar cell bodies including their synaptic processes in the inner plexiform layer were high in taurine content. However, the pigment epithelium and distal parts of glial cells had only low levels of immunostaining. Recently, it has been demonstrated that there are differences between the immature (14-day old) and mature (12-week) rat in the location of taurine-like immunoreactivity in the retina93. In the retina of the immature rat, taurine-like immunoreacti~ty was observed primarily in the outerplexiform layer with onIy weak reactivity in the photoreceptor cell layer. However, in the mature rat, the cellular location of taurine-like immunoreactivity was found to be the opposite, i.e., present mainly in the inner segments of the photoreceptor cell layer but only weak reactivity observed in the outer plexiform layer. Localization of taurine-like immunoreactivity in the retina of the canary is similar to the immature rat in that the most intense reactivity is in the outer plexiform layerg3. However, taurine-like immunoreactivity was also observed in the photoreceptor cell layer, inner nuclear layer, and weakly in the ganglionic cell layer. The taurine content of the retina changes with age in some species. In the retina of the mouse taurine levels increase dramatically between day 12 and 16 (120 -+ 180 pmol/g dry retina) just after the eyes open6i. In the rat similar postnatal increases in retinal taurine content are observed and reach a maximum at approximately day 30 (Ref. 143). The taurine levels then decrease between 3 and 6 months of age in the rat16’17. Sturman and colleagues244 refer to their unpublished observations that retinal taurine content also increases in the gerbil and cat during development. In the chick retina, the observations reported in the literature are conflicting. Gupta and Mathurso report that taurine levels increase in the embryonic period if calculated on a wet weight basis but remain constant if based on protein”. After the chick hatches the taurine levels increase to a maximum at approximately day 14 (based on protein) and then decrease5’. However, Pasantes-Morales and colleagues’78 report that during incubation prior to hatching the taurine content (based on wet weight) of the chick retina decreases from day ll20. After hatching the taurine levels of the chicken retina increase based on wet weight (posthatching: day 1, 7.33 pmol/g; day 7,7.79 PmoYg; day 30,8.39 PmoVg and adult, 8.91 pmol/g)i7* (and also based on protein, personal communication with Pasantes-Morales). Taurine levels measured in the retinas from 6-day-old chickens reared in the dark were found to be approximately 90% greater than in the retinas of animals exposed to either constant light or a normal day-night cycle’78. Also, at day 3 the incorporation of [35S]taurine
153 into retinas of chickens reared in the dark was greater than in the animals exposed to a normal day/night cycle’78. Prior to day 3 the taurine levels were similar under the two conditions of light and darkness. It was suggested that light increases the release of taurine’78. No changes in the content of taurine in the monkey retina are reported for the time period from late gestation to maturity244. 3. SYNTHETIC ENZYMES
Initially the enzymatic synthesis of taurine produced much confusion and controversy due to a number of possible synthetic routes proposed for mammalian tissuessO. However, it is now considered that the primary pathway for synthesis is mediated through cysteinesulfinic acid (CSA) and thus a specific decarboxylation reaction is required to produce hypotaurine which is then converted to taurine. In the chicken, ox, and rat retina it has been established that taurine synthesis definitely occurs and that cysteinesulfinic acid decarboxylase (CSAD) is a key emyme59,142,147,213~ It has also been demonstrated that CSAD activity is regulated by the presence of light. CSAD activity and taurine levels are reduced in the light-adapted frog retina while increased in the darkadapted retina 76P92V159,160. Antibodies to CSAD have been produced and CSAD immunoreactivity is found in photoreceptor cells (both rods and cones) and bipolar, amacrine and ganglion cells in the rat retina’18 while in the rabbit retina the greatest CSAD immunoreactivity is located in the inner nuclear layer and the ganglion cell layer1’7V268.Compared to the rat, the human, monkey, and cat have much reduced CSAD activity in their livers (relative activity: rat 100, human 0.07, monkey 1, cat 1 (Ref. 47)) and it can be presumed that the levels of CSAD in the retina are similarly reduced or not present. Definitive measurements of CSAD activity in at least these 3 species have yet to be obtained for the retina. Also of interest is the observation that in the brain of several species (including rabbit, rat, monkey and human) the levels of taurine decrease with age either during fetal development or immediately after birth whereas at least in the rat brain the activity of CSAD is reported to increase with age2*‘79*“’ although these data should be viewed with caution (see below). This inverse relationship between taurine levels and CSAD activity in the brain is not observed in the retina of the rat. As discussed above, taurine levels in the rat retina increase with age up to day 30 (Ref. 143). CSAD activity in the rat retina also increases with age-approximately 3-fold between 10 and 30 day8 after birth’82. Taurine levels within the various tissues of the eye, however, do not appear to correlate with CSAD activ-
ity 59. While the retina has the highest content of taurine compared to the lens, iris-cillary body or cornea, the cornea contains the highest activity of CSAD. Heinlmslki 59 thus suggests that an intraocular transport mechanism may be involved in the regulation of taurine levels within the various ocular tissues. It should be pointed out that some of the CSAD and taurine assays have been fraught with error due to methodological difficulties. First, the CSAD assay has been questioned especially in the older literature because CSA is also decarboxylated by glutamate decarboxylase depending upon the substrate concentration (reviewed in Ref. 68). For instance, concentrations of lo-48 mM CSA were used to measure CSAD activity in the rat brain2,1W and ocular tissues59*‘82.However, the levels of CSA in various regions of the rat brain have been determined to be in the range of 0.01-0.29 mM (reviewed in Ref. 68). Thus, assaying for CSAD in the presence of CSA at one or more of magnitidue higher than its physiologic substrate concentration may yield spurious results due to the observation that glutamate decarboxylase may also decarboxylate CSA when CSA is added to the incubation system at such a high concentration. The resolution as to whether CSAD correlates or does not correlate with taurine levels in brain, ocular or any other tissue must be reevaluated by utilizing proper enzymatic methodologies. Second, ninhydrin positive materials (e.g. glycerophosphoethanolamines) that may co-migrate with taurine on the amino acid analyzer can yield falsely elevated taurine levels in tissue samples52*248. Other enzymes involved in the synthesis of taurine and reported to be present in the retina (of at least some species) are cysteine dioxygenase (cysteine oxidase) which catalyzes the conversion of cysteine to cysteinesultjnate42J42J83 and hypotaurine dehydrogenase which oxidizes hypotaurine to taurine41 possibly through a disulfone intermediate45. Cysteine dioxygenase has been demonstrated to be primarily localized to the inner segments and photoreceptors in the ox retina but appears to be absent in the ROSS’~~. 4. TAURINE BINDING PROTEINS
Further evidence of a role for taurine in the retina is the presence of two binding proteins specific for taurine. The two binding sites (high-affinity site, 7 PM; low-affinity site, 330 PM) demonstrated in the rat are sodiumdependent and are thus perhaps involved with taurine uptake sites’“. It is suggested due to the similarities between taurine binding and taurine transport, i.e. sodium dependence and approximate agreement between transport and binding constants, that the binding processes observed in the rat retina are associated with transport
154 systems for taurine’34. This conclusion is supported by the earlier observations of Ldpez-Colomt? and PasantesMorales’38 who observed in a chick retinal membrane preparation a highly Na+-dependent dissociation constant of 9.32 ,uM, a value which is in the same order of magnitude for the K,,, kinetic constants for the high-affinity uptake system for taurine transport in brain slices”* 12’ and synaptosomes62*95’221. Mpez-Colomt and Pasantes-Morales 13’also measured [3H]taurine binding in the absence of Na+. This binding is extremely low. Arguments are presented which rule out the interpretation that the observed Na+-independent [3H]taurine binding is an interaction with postsynaptic receptor sites in the chick retina. In other experiments by Salceda and Pasantes-Morales2r5, a single binding site for taurine with a dissociation constant of 98 ,uM was demonstrated in the rat retina when Na+ was omitted from the incubation medium. Again this Na+independent taurine binding demonstrates properties different from those generally attributed to postsynaptic binding to receptors such as has been observed for the amino acid neurotransmitters glycine, glutamate and y-aminobutyric acid. Evidence has also been reported that taurine interacts with [3H]strychnine binding sites in the rat2r6 and bovine25 retina. Taurine is equipotent with glycine in inhibiting high-affinity, low-capacity [3H]strychnine binding to retinal membranes in the rat216 but has less effect than glycine in the bovine retina25. Schaeffer and Anderson2r6 have suggested that taurine may have a specific binding site in the rat retina and/or may interact with glycine binding sites.
It has also been demonstrated tht metabolic inhibitors and temperature greatly influence the uptake of taurine in the retina212. Addition of either 2,4_dinitrophenol or ouabain significantly reduces taurine uptake as does lowering the incubation temperature to 4 “C. Observations that taurine increases (in a sodium-dependent fashion) the ouabain-sensitive apical Na+K+ pump in retinal pigment epithelium were recently reported220. In these electrophysiologic studies it was also demonstrated that taurine inhibits the apical positive transepithelial potential in the bullfrog retina. These studies thus suggest that taurine is directly involved in an electrogenic sodium/taurine cotransport mechanism. The distribution of radioactive taurine taken up by the retina has been studied by autoradiographic techniques. In the mouse retina, [35S]taurine accumulated, after either intravitreal or intravascular injection, in the outer nuclear layer, the inner nuclear layer, and the Mtiller cell processes20c while in the newt retina, amacrine cells found within the ganglion cell layer accumulated [35H]taurine’2. In the rat and cat, autoradiography showed the accumulation of [3H]taurine in Mtiller, photoreceptor, and amacrine cells201,234. 6. RELEASE MECHANISMS
FOR TAURINE
Perhaps the first identification of a function for taurine was in the chick retina where it was observed that depolarizing agents and light stimulate the release of radioactive taurine and thus it was suggested that taurine may be involved in the mechanism of light excitation and/or dark adaptation’79Y194’1W. Flashes of light have also been shown to release endogenous taurine from the rabbit retina151*‘53. 5. TAURINE UPTAKE SYSTEMS The site of the release of taurine has been identified as the rod outer segments (ROSS) in the frog retina214 Along with the high-affinity binding site for taurine and by indirect evidence as the photoreceptor layer of there are also numerous studies demonstrating the the chick retina1ss*211.Additional evidence that taurine presence of a high-afhnity transport system for taurine has a role in the photoreceptors was demonstrated by in the retina and pigment epithelium of the rat, toad, frog, chick, cat, rabbit, baboon, and human39Y44,46*61s5Y Schmidt222 who observed that the light-evoked release of 105,106,152,212,215.223,224,227,228,234-236 taurine is present in isolated cat and rat retinas but is . High-affinity transabsent in the photoreceptorless retina of the Royal Colport has also been demonstrated in chick embryo retinal lege of Surgeons (RCS) rat. Thus, with the above obneurons, glial cells and retinoblastoma cells in culturel’ servations plus the depressant effect of taurine on reti1W*270*271. A low-affinity taurine transport system and/or nal neuronal activity36*86,170,it has been suggested that a non-saturable uptake mechanism has been reported for certain of the above animal species39,152,212,227,u4Y235, taurine may be an inhibitory neurotransmitter 144*145*202 although there is evidence to the contrary15*. For exam270*271.However, the presence of two transport sysple, while high potassium and the ionophore A23187 terns appears to depend upon the age and the species evoke the release of radioactive taurine from whole chick studied. For instance, Salceda2i2 has shown that the retina, the release of taurine from a synaptosomal fracadult rat and the 15-day embryo chick have two transtion was unaffected by these agents’39*188.Veratridine port systems for taurine while the 20- and 30-day-old rat also had no effect on releasing taurine from subcellular and the adult chick have only the low-affinity transport retinal fractionsls8. Thus, in these studies it was consystem.
155 eluded that taut&e was not being released from nerve terminals and hence is not a neurotransmitter139’1ss. Other effecters of taurine release from the retina are the calcium ionophore X537A’93 and electrical stimulation 224. However, it appears that electrical stimulation of taurine release may be due to non-specific tissue damageu3. Also, when taurine release is compared to the release of the putative amino acid n~uro~ans~~ers, there are significant differences such as: (a) light stimulates the release of taurine from the whole chick retina but has no effect on GABA, glutamate, or glycine release’“; (b) colchicine inhibits the stimulated release of taurine by potassium, veratridine, and glutamate in the chick retina but has no effect on GABA release’95; and (c) cytochalasin B has a significant effect on the glutamateand veratridine-stimulated release of taurine but only a slight effect on GABA releaselp5. The potassium-stimulated release of [3H]taurine from the rat retina is only partially calcium-dependent (contrary to j3H]glycine release which was tested in the same tissue preparation)uJ and occurs only after the stimulus (IL’) is removed from the superfusing medium, i.e. a slow delayed release=’ 176,235.Dopamine also affects both the spontaneous and K-evoked release of [3H]taurine from the superfused rat retina203. When dopamine and K+ are added simultaneously to the isolated retina the delayed release of taurine is not affected, However, the delayed release of taurine can be effectively blocked if dopamine is added to the predation after the K+-stimulus. Effecters such as glutamate, aspartic, cysteic acid, kainic acid and N-methylaspartate which stimulate release of radioactive GABA an&or glycine have no effect on taurine release from isolated, perfused chick retinala. These results suggest that taurine release is occurring through a different mechanism(s) than the one accepted for the classic neurotransmitters and thus tend to diminish the possibility that taurine is a neuro~ans~~er in the photoreceptors. However, more recent studies in the rabbit retina suggest that taurine may be a neurotransmitter in amacrine cellist’. Alternatively, it has been suggested that taurine may be involved in the contractile processes of the photoreceptors due to the inhibition of the light-stimulated release of radioactive taurine by colchicine, vinblastine, and cytochalasin B which are known to interfere with contractile eventslm. Finally, recent studies demonstrate that the release of radioactive taurine from chick retinas occurs through two mechanisms43*‘76. The minor component of the release mechanism is calcium-dependent and related to membrane depolarixation, while the major component is chloride-dependent and calcium-independent and also dependent upon an increase in cell volume43T176.It is
postulated that two different cell types or in~a~~~ar pools may be involved with taurine release from the retina. Pasantes-Morales and her colleagues have thus concluded that changes in ceil volume are responsible for the taurine released when retinal preparations are exposed to high K+ inundations. Therefore, the release of taurine is not due to an event brought about by K+evoked depolarization. In their experiments, if depolarization was causing ]3H]taurine release then the absence or reduction of Cl- in the medium should have increased depolarization with a subsequent increase in [3H]taurine release which was not observediW. Not only is taurine released from the retina under a variety of conditions, but taurine itself also affects the release of the neurotransmitter acetylcholine38. It has been demonstrated in the rabbit retina that the lightevoked release of acetylcholine from bipolar cells and/or amacrine cells is abolished by 1 mM taurine. However, the spontaneous release of acetylcholine was not affected by taurine. Strychnine blocked the effects of taurine. It was concluded from these studies that choline@ activity in amacrine cells in the rabbit retina may be influenced by taurine. 7. EFFEXTS OF TAURINE
ON THE ELECTROREZTINO-
GRAM
In the 1970’s when taurine was first proposed to be an inhibitory neurotransmitter in the retina a number of studies were conducted which measured the effects of taurine on the electroretinogram (ERG). Physiologic doses of taurine depress the b-wave of the ERG in the chicken and frog retina9’23’131’170’1%‘252’253 but are without effect on the a-wavew~170V196~2J2. The effects of taurine on the ERG are antagonized by strychnine but unaffected by picrotoxin which stands in exact contrast to those effects for GABA and led to the postulation that tam-me may be exerting its effects ~sts~aptica~y~. Intracellular recordings from the mudpuppy and frog retina have demonstrated that ganglion cells are sensitive to taurine and taurine may be involved in the OFF response of ganglion cells”“‘. It has also been demonstrated by intracellular recordings that taurine and glytine are equally effective in inhibiting spike activity in turtle and cat ganglion cells’0,22. However, in electrophysiolo~c studies involving the cat retina a tr~smitter role for glycine in the inner retina was favored over taurine because of the presence of a transport system for [3H]glycine and localisation of [3H]glycine in amatine cells. Similar results were not obtained for taurine**. Finally, it has been recently suggested by electrophysiological and morphological experiments that tau-
156
rine has a protective effect against hypoxia in the retinam. Taurine (1 mM) produced a significant recovery in the b-wave amplitude in dark-adapted, perfused bovine eyes after exposure to hypoxic conditions. In addition, the mitochondrial damage that was observed in the inner segment of the photoreceptors after an ischemic/ hypoxic episode was reduced after treatment with taurine (1 mM). 8. RETINITIS PIGM~~OSA
The late Dr. And& Barbeau, who had a keen interest in determining the function of taurine, stated that, unless a disease is associated with taurine, interest in this sulfi~r amino acid will wane. Therefore, great hopes for taurine in preventing pathology were raised when it was observed that both the levels of taurine in platelets and plasma3~4*25fand taurine uptake in platelets395,ti were decreased in a subpopulation of patients with retinitis pigmentosa (RP). Blood levels of taurine were also demonstrated to be decreased in specific genetic subclasses of RP patients” although normal values were reported in earlier (in plasmam) and later studiesZ5. On the contrary, patients who expressed an autosomal dominant RP with both rods and cones equally disturbed (R-type) had elevated plasma taurine levels65. The evidence for the differences in the uptake of taurine in the RP patients compared to controls has also been shown to be in~ns~tent. Voaden and colleagues2J6 found no difference in taurine uptake in platelets of simplex and autosomal dominant RP patients in contrast to Airaksiuen et al.3, but found that the capacity of the high-affinity transport system was higher in patients with X-linked hemizygote and multiplex disea#‘. Whether these are indeed changes in taurine uptake or changes in blood homeostasis of the RP patient remains to be clarified”‘. However, even with the confusion relating to the value of taurine measurements in RP patients, taurine supplementation has been utilized in an attempt to improve the clinical situation’@. Unfortunately, taurine supplementation of l-2 g/day for one year in RP patients did not produce any si~fi~nt clinical change. A different approach utilizing lymphoblastoid cells which possess a hip-affinity uptake system for taurine has been used to potentially monitor RP patients2665267. It was demonstrated that l~phobl~toid cells from RP patients differ from control cell lines in their ability to take up taurine266. The V,,,, for taurine uptake in cell lines from RP patients is lower while the K, is greater than values obtained for control cell lines. Finally, the question was posed whether urinary taurine can be used as a marker for RF’18.The answer is: no. Dr. Barbeau would have been disappointed.
9. RETINAL DEGENERATION
IN ANIMAL MODELS AND
HUMANS DUE TO TAURINE DEFICIENCY
Animal models of hereditary retinal degenerations have been studied for their retinal taurine content. However, it is concluded that in rd mice, RCS rats, and Irish setter dogs with rod-cone dysplasia the loss of taurine in the retina is secondary to the loss of photore~ptor cells’62*22s9227. In the Abyssinian cat with dominant rodcone dysplasia there appears to be no abno~~ity in taurine uptake or levels in the pigment epithelium compared to controls257. While the data are controversial regarding the relationship between taurine and RF’ there is no doubt that retinal pathology can be induced in animal models by a dietary taurine deficiency. The first report of retinal degeneration associated with a taurine deficiency was by Hayes and colleagues56 who demonstrated that both in the kitten and adult cat a central retinal degeneration appears after 3 months of diets lacking in taurine. Their results provided the stimulation for research which ultimately generated evidence that dietary taurine is necessary for the human species. This evidence, although not proven, prompted infant formula manufactures in the U.S.A. and abroad to add taurine to their synthetic diets. Numerous studies have been performed with the cat as an animal model for taurine deficiency and all are in basic agreement that taurine is an essential component of the diet, and that its absence leads to severe retinal damage involving the outer segments of the photoreceptors and the tapetum 8,15,19,2?,57,?8,175.226,229,230,240,242,245, a7*262$263. Specifically, the damage manifests itself in severe disorganization and in a reduction in thickness of these areas; the disk membranes also demonstrate disorientation plus vesiculation and swelling. The tapetal cells in the taurine-deficient cat contain electron-dense globules and appear either shrunken or swollen depending upon their location either in the inner or outer layers. In casein-fed cats which subsequently become taurine deficient the amplitude of the b-wave of the ERG is reduced and the cone b-wave implicit times are delayed81* 82,u)6_In other studies the ~plitude of the a-wave was also reduced21~78~8*~82~175,206, Loss of rhodopsin in certain regions, specifically the horizontal streak area extending from the central retina to the nasal retina which normally contains high rhodopsin content, have been observed in the taurine-deficient catsl. In the infant rhesus monkey taurine deficiency produced by feeding a taurine-free or low-taurine infant formula also produces retinal abnormalities, specifically, a diminution of the cone ERG and degeneration of the
157 ultrastructure of the cone photoreceptors resulting in loss of visual acuity”,154-157,246.However, when placed on a diet deficient in taurine infant ccbus and cynomolgus monkeys appear to conserve taurine to a greater extent than the cat and while growth was depressed retinal degeneration was not observed5*. Taurine deficiency is more difficult to produce in the rat, since this animal is capable of synthesizing taurine in sufficient quantities from endogenous precursors and thus a taurine-deficient diet has no observable effect. However, the taurine analogue and transport inhibitor, guanidinoethanesulfonic acid (GES), when placed in the drinking water rapidly (- 2-3 weeks) depletes the body stores of taurine in the rat63,72. When the rat is treated with GES, high-affinity taurine uptake into the retina is competitively inhibited’0’*2a“ and the retinal levels of taurine are diminished to approximately 30-40% of control values%,g,2as. pups of nursing mothers treated with GES have retinal levels of taurine 50-70% of controls9*. Retinal pathologies including both changes in the ERG and alterations in morphology are also observed in the albino rat when the taurine levels are decreased with GES treatment. Changes in the ERG include decreases in amplitude of the a- and b-wave32,53*99,2059207 while damage to the photoreceptors includes a reduction in the size of the layer, disarray of the disks and disk membranes, swollen inner segments and nuclei, and accumulation of vesicular membrane-bound profiles within the basal region of both rods and cones53,104,191*un, These abnormalities frequently lead to cell death. In the albino rat, the pigment epithelial cells were shown to be damaged by taurine depletion. In the cat, however, no changes (or less severe changes) were observed in this tissue (Ref. 57; also discussed in Ref. 104). While it is well documented that taurine depletion produces morphologic changes, such as photoreceptor cell loss, in the retina of the albino rat, similar changes are not observed in the retina of the pigmented rat although a reduction in ERG amplitudes does occurm. Thus, it is suggested that in the albino rat light may increase the degenerative changes induced by taurine depletion 102*104,u)5*208, 231.The effects of taurine depletion on the ERG, retinal structure, and the interactions between taurine deficiency and ambient lighting are reviewed by Lake”“‘. /?-Alanine, also a taurine transport inhibitor, when injected intraperitoneally into adult rats produced disruption of the photoreceptor structure”’ but had no significant effects on taurine levels in the retinalo3. The above background material leads to the question how taurine deficiency affects human vision. The evidence is somewhat scanty and not definitive. However, infants and children fed totally by parenteral nutrition which was lacking in taurine developed low plasma tau-
rine levels accompanied by reduced amplitudes in the ERG and morphologic changes observed by ophthahnosThese abnormalities were corrected in 7,48,49*254. COPY some of the children when taurine was added to the infusate. It is thus suggested that taurine is a conditionally essential amino acid in very specific nutritional circumstances such as total parenteral nutrition. The obvious but unanswered question is why all the abnormalities in the children were not corrected. Contrary results as to the benefit of taurine supplementation have also recently been published13. In these experiments, taurine supplementation (0.4% in diet) was visual function found to cause additional deterioration rotein enas monitored by ERGS in rats which wer ergy malnourished. Taurine supplementati n did not have any adverse effects in control rats or rats which “:: at the above were pair-fed. It was concluded that tauri dietary level is conditionally toxic in low protein diets. Thus, these investigators suggested that the status of the patient relative to his/her ability to regulate taurine in diseased or malnourished tissues be assessed prior to taurine supplementation. Finally, in considering taurine as a conditionally essential nutrient as previously discussed, Lima and colleagues”5*“6 have demonstrated that taurine has a stimulatory effect on the outgrowth of retinal explants in goldfish. The effect of taurine is concentration dependent at low concentrations (l-4 mM) but becomes inhibitory to explant regeneration at high concentrations. The time relationships between addition of taurine and growth of the explants suggest that there is a critical period for taurine to be effective. However, the mechanism for the effect of taurine on explant regeneration is unknown, 10. POSSIBLE FUNGI-IONS OF TAURINE
In recent years taurine function in the retina has centered around 3 possibilities: (1) protection of the photoreceptor-based on the shielding effects of taurine on ROSS exposed to light and chemicals; (2) regulation of Ca2+ transport-based on the modulatory effects of taurine on Ca2+ fluxes in the presence and absence of ATF; and (3) regulation of signal transduction-based on the inhibitory effects of taurine on protein phosphorylation. 10.1 Protection of the photoreceptor Exposure of isolated ROSS obtained from frogs to either continuous illumination or chemicals such as ferrous sulfate produces gross morphological changes evidenced by severe disruption of the structure characterized by swelling and vesiculation. In isolated frog ROS preparations taurine decreases light-induced damage in a dose-
158 dependent
(5-25 mM) fashion168*171*173.Twenty-five
taurine lowers the percentage ues lower than those normally controls.
Other amino acids such as glycine and GABA
had a similar present
protective
effect but, since they are not
in high concentrations
in the ROSS, this physi-
ologic role was not attributed protects
mM
of disrupted ROS to valobserved in dark-adapted
the ROSS against
to thernla.
disruption
but only if 100 PM zinc is present; in the absence
by ferrous
taurine
also
sulfate
has no effect
of zinc171V173.
Both light and ferrous lipid peroxidation
cause an increase
by malonaldehyde
involving
by taurine174. ferrous
sulfate
in
forma-
frog ROSS. The light-induced
is not affected
the experiments
sulfate
as measured
tion in the isolated peroxidation
Taurine
However,
lipid in
the increased
the
incubation
system.
At
high
Ca*+
concentrations
(1.4-2.5 mM) taurine is inhibitory in the chick, frog, and rat113.13*.13’,1~,16’,169,171while at low ca2+ concentra_ tions (10-100 PM) and in the presence stimulatory
of ATP taurine
Presently, there is only speculation as to the physiologic meaning of the biphasic effects of taurine on Ca*+ fluxes in the ROS. Assuming visual transduction
that Ca*+ has a role in the
process it has been suggested that the
taurine-stimulated uptake of Ca*+ into disks is a means to remove Ca*+ from the cytoplasm”‘. A similar argument for the role of taurine also been
in the nerve
taurine
could perhaps
terminate
Ca*+-dependent
It is speculated that the protective effect of taurine on isolated frog retinal membrane structures against peroxidation-induced damage is due to its interactions with ion permeability and/or water accumulation in the membranes 171~174~192 and not due to any effects on membrane
dria) by a process which is energy dependent
10.2. Regulation of Ca2+ transport A second possible function for taurine in the retina is It has been demonthat it regulates Ca*+ transport. strated that taurine has a biphasic effect on Ca*+ accumulation depending upon the concentration of Ca*+ in
has
Ca*+ uptake into mitochondria located within the nerve terminals which is stimulated by transmitter
regulating ionic fluxes it has been suggested that taurine may reduce the oxidative and peroxidative products produced in the retina and thus attenuate their damage and/or prevent cell death%‘. One of these products is hypocholorous acid which is effectively neutralized by taurine119’264.
terminal
proposed169.
lipid peroxidation was also accompanied by water accumulation which was decreased by taurinel’*.
fluidity 149. Thus a function for taurine as an osmoregulator has been suggested. This conclusion is based partly on the observations that the light-induced damage in the ROSS requires the presence of bicarbonate, sodium, and chloride ions and possibly involves proton fluxes and regulation of the pH of the ROS. However, further complicating the possible mechanism for the protective effect of taurine is the observation that the addition of taurine prevents the disruption of ROSS in a calciumfree medium and modifies Ca*+ fluxes within these structures’a”71. These data thus suggest that Ca*+ and taurine are also intimately involved in a mechanism to maintain and stabilize the structural and functional integrity of the photoreceptor membranes. In rats light-induced ‘photoreceptor disruption and loss was not prevented by the administration of taurine (5%) in the drinking water 259. The protective effects of taurine on ROSS are summarized by Pasantes-Morales et al. 181. As a corollary to the possible function of taurine in
is
90,111,112,114,121-128,131,133,137,1W,169,171,187
removed
release’28~169. In either into a subcellular
organelle
neuro-
case Ca*+ is being (disk or mitochon(requiring
ATP) and stimulated by taurine. A functional role for the inhibitory effects of taurine on Ca*+ flux in the absence of ATP and at high Ca*+ concentrations (in the millimolar range) is more difficult to envision. It has been suggested that a calcium-calcium exchange process is occurring under these conditions without a net uptake of calcium137*161*232.However, the physiologic meaning of the inhibitory effect of taurine on this process remains to be clarified. When a series of taurine analogues were tested for their effects on 45Ca2f accumulation in a rat retinal preparation at high Ca*+ concentration (1.4 mM), it was determined that only taurine and a-sulfo-/l-alar&e are inhibitory13*. Addition of the calcium ionophore A23187 to the retinal system had no effect on 45Ca2+ accumulation which suggests that the 45Ca2+ accumulation was due to 45Ca2+ binding to membrane surface components rather than being transported into vesicular components of the retinal preparation13*. When A23187 was added to the retinal preparation in the presence of (*)trans-2aminocyclohexanesulfonic acid the accumulation of 45Ca was further increased by a factor of 2 beyond the stimulation observed with the cyclic taurine analogue alone, indicating that the cyclic taurine analogue might have altered Ca*+ binding sites within some vesicular entities. These modifications might have then allowed more Ca*+ to be bound within the vesicles when additional 45Ca2+ was made available by the membrane-disrupting properties of the ionophore A23187. The specificity of taurine in stimulating ATP-dependent Ca*+ uptake has been studied extensively. Numerous analogues of taurine of widely varying chemical structures have been used to determine the structural requirements for stimulating Ca*+ transport in the rat retina. Modifications of the sulfonic acid moiety of tau-
159 rine are well tolerated and close structural analogues of taurine such as hypotaurine, 2-aminoethanephosphonic acid, and Zaminoethylhydrogen sulfate are stimulators of ATP-dependent Ca2+ uptake’n’lu. Modifications of the amino moiety of taurine are less tolerated and thus isethionic acid and guanidinoethanesulfonic acid do not have any stimulatory activity121F’23.The taurine analogue with a 3 carbon backbone between the amino and sulfonic acid moieties is inactive122’126while aminomethanesulfonic acid is an inhibitorlz. Glycine and p-alanine are stimulators’22. Analogues of taurine have also been tested in frog ROSS for their effects on ATR-dependent Ca2+ uptake. Cysteinesuhinic acid and hypotaurine stimulated Ca2+ uptake although to a lesser extent than taurineW”64. Conflicting (stimulatory or no effect) data have been presented for /?-alanine and glutamic acid90*161Y187. Guanidinoethanesulfonic acid, GABA, glycine, histidine, and proline had little or no effect in the system which utihzed a frog ROS preparationW*1&1*‘87. Compounds which contain the taurine structure within a ring configuration and thus are conformationally more rigid than taurine have been tested for their effects on ATP-dependent Ca2+ uptake in rat retinal preparations 112V114.Four analogues have been synthesized: ( +)WWLS-and (*)&2-aminocyclohexanesulfonic acid (TAHS and CAHS), and (?)trans- and (+)c&Zaminocyclopentanesulfonic acid (TARS and CARS) (Fig. 1). CAHS was shown to be a stimulator of ATP-dependent Ca2+ uptake though not as potent as taurine while TAPS and TAHS were potent inhibitors with I,, values in the PM range (Table I). CARS was also an inhibitor though quite weak (Iso = 1.8 mM). These unanticipated results cannot be explained by the differences in the intraatomic distances between the nitrogen of the amino and the sulfur of the sulfonic acid moieties. The distances between the heteroatoms of TARS and TAHS was 4.0
A if the functional groups for the molecules are placed in an equatorial-equatorial conformation for TARS and in a diaxial orientation for TAHS (Fig. 1). In CAHS the intra-atomic distances were 3.0 and 3.1 A in either of the possible conformations (axial amino-equatorial sulfonate or equatorial amino-axial sulfonate). CARS was erroneously predicted to be a stimulator of ATF-dependent Ca2+ uptake based on an intra-atomic distance of 2.7 A for the heteroatoms rater than an inhibitor. Thus, it was suggested that the size of the alkyl moiety and its relative position in the molecule contributed to the differences in the biological activities112. A second series of taurine analogues in which the sulfonic acid moiety was replaced with a sulfone moiety was also synthesized and tested for activity in the ATP-dependent Ca2+ uptake system in rat retinal preparations”‘* ‘13 (Fig. 2). 2-Aminoethylmethylsulfone (ARMS), (&)3aminotetrahydrothiopyran-1, l-dioxide (AI’S), and( +)3aminotetrahydrothiophene- 1,l-dioxide (ATS) , compounds which contain a primary amine, were found to be more potent stimulators of Ca2+ uptake than taurine. However, two analogues, thiomorpholine-&l-dioxide (TMS) and N-methylthiomorpholine-l,l-dioxide (M-TMS), which do not contain a free amino moiety but
TABLE I Effects of taurine and cyclic taurine analogues on ATP-dependent Cd’ ion uptake by a rat retinal membrane preparation Data are presented as means f S.E.M. Means with different superscripts are significantly different (P < 0.05) from each other. (Reprinted from Ref. 112). Compound
Taurine TAPS CAPS TAHS CAHS
Concentration required for 50% inhibition (wW 39 f 5” (5) 1775 + 403b (4) 86 2 13’ (6) -
Concentration required for 50% stimulation (mW 8.1 + 1.4 (7) 6.; +- 3.2 (4)
Fig. 1. Structures of the diasteromeric racemates of 2-aminocyclohexane sulfonic acid and 2-aminocyclopentane sulfonic acid. ‘lkvo possible conformations are shown for each cyclic analogue. (Reprinted from Ref. 112).
160 the distinct possibility that the sulfones are exerting stimulatory effects through different mechanisms.
H3C-S 0
The effects of various taurine analogues in combination with taurine have also been tested in the ATP-de-
I
pendent
//\
0
mine
I-AMINOETHVLMETHVL SULFONE
N-METHVLTHIOUORPHOLlNE-
THDMORPHOLINE1.1~DIOXIDE
(AEM.
l.l-DIOXIDE
/
Ca2+ uptake system of the rat retina to deterrelationships and possible synergistic
kinetic
effects’31’133. TAPS (Fig. 1) and 1,2,3,4_tetrahydroquinoline-&sulfonic
acid (THQS),
uptake,
when tested
non-competitive
c
in combination
separately
of Ca”+
were determined
with respect to taurine were demonstrated
to be
and when tested
to be strongly
syner-
gistic. Kinetic data suggest that TAPS and THQS have a similar mode of action, i.e. mutually exclusive133. ATS
s03H
(Fig. 2) and (*)piperidine-3-sulfonic
TAURINE (TAU)
//\ 0
0
//\
0
PHENE-l.l-DIOXIDE
CAPS)
(ATS)
Fig. 2. Structures of taurine and sulfone analogues of taurine. (Reprinted from Ref. 113).
a secondary or tertiary amine placed structure, were inactive (Table II).
within
the ring
The findings that the sulfone analogues of taurine which contain primary amines (AEMS, APS and ATS) are potent stimulators of ATP-dependent Ca2+ uptake are of considerable interest, since sulfonic acids at physiologic conditions are ionized while sulfones are nonionized. Sulfonic acids and sulfones are not considered to be classical isosteric functional groups. Thus, there is
TABLE II Effects of taurine and sulfone analogues of tourine on ATPdependent Ca2+ uptake by a rat retinal membrane preparation
Data are presented as means + S.E.M. Taurine and analogues (see Fig. 2) were tested at a tinal concentration of 20 mM. Means with different superscripts are significantly different (P < 0.05) from each other. (Data are reprinted from Ref. 113). Compound
Cd’ uptake (nmollmg protein)
Control Taurine AEMS ATS APS TMS M-TMS
1.6 4.7 7.8 9.6 7.3 3.0 1.9
+ 2 2 2 f + +
0.2’ 0.4b 1.2c.d 1.3” 0.6d 0.Y.b 0.4”
an ag-
Ca2+ up-
take system,
exclusive
were also shown to be mutually However,
while the combi-
nation of taurine plus ATS is additive the combination of taurine plus PSA is synergistic. The relationships of the effects of these compounds on ATP-dependent Ca’+ uptake are shown in Fig. 3.
(t)3-AMINOTETRAHVDROTHIO-
PVRAN-l.l-DIOXIDE
acid (PSA),
onist and partial agonist in the ATP-dependent when tested in combination.
(~)~-A~~~NoTETRAHvDR~THIo-
a weak inhibitor
w-TMS)
CTMSLO
NH2
0
their
(19) (19) (6) (9) (3) (7) (4)
Taurine has an opposite effect, i.e. inhibitory rather than stimulatory, on Ca*+ accumulation when the Ca*+ concentrations are elevated to the mM (1.4-2.5 mM) range 113,132,137,166. At a concentration of lo-20 mM, taurine inhibits Ca*+ accumulation by 2575% depending upon the species and the retinal preparation. Various analogues of taurine have also been tested for their effects on ATP-independent Ca*+ accumulation at high (1.4-2.5 mM) concentrations of Ca*+. In frog ROSS 10 mM glycine, GABA, and p-alanine had no effect13’ while in various subcellular fractions of the chick retina 10 mM glycine and /3-alanine had a slight effect’&. In the chick GABA and glutamate had no activityl@. In the rat retina when tested at a concentration of 20 mM the sulfone analogues of taurine, AEMS, APS, and ATS (Fig. 2) - stimulators of ATP-dependent Ca*+ uptake - were more potent inhibitors of ATP-independent Ca*+ accumulation than taurine itself113. The sulfone analogue of taurine containing a secondary amine, TMS, also was inhibitory equipotent with taurine; however, the tertiary amine derivative, M-TMS, was inactive’13. TAPS and TAHS (Fig. 1) have been shown to be stimulators of ATP-independent Ca*+ accumulation at a high (1.4 mM) Ca*+ concentration132. This is directly opposite to the effect observed in the ATP-dependent Ca*+ uptake system at low (10 PM) Ca*+ concentration in which TAPS and TAHS were potent inhibitors”*~‘t4. CAPS and CAHS have no effect on Ca*+ accumulation at high Ca*+ concentrationt3*. The studies utilizing taurine and taurine analogues as modulators of Ca*+ uptake and/or accumulation demonstrate the specificity for the taurine structure in this phys-
161
iologic process.
In attempting
taurine
retina
in the
clearly emphasize
to define a function
structure-activity
for
relationships
the uniqueness
and importance of the
taurine structure in this tissue. It has also been demonstrated
in Arrhenius plots that
TABLE III Effect3 of taurine and taurine analogues on incorporation of radioactivephosphate into rat retinal membrane proteins TAPS and TAHS could not be tested at 20 mM due to lack of solubility in aqueous solutions. Structures of analogues are presented in Figs. 1 and 2. (Data compiled from Refs. 112, 113, 123).
taurine affects the transition temperature of ATP-dependent Ca*+ uptake in rat retinal membrane prepara-
~~
tions?*‘. Taurine (20 mM) elevates
Compound
perature
from
the transition
17.9” to 25.4 “C while
lowering
tem-
apparent activation energy for Ca2+ uptake. Interpretation of these results is only speculative tion is that taurine may be inducing change within the membrane.
but the implicaa conformational
Taurine may be causing a
change within the structure of the membrane by directly affecting the physical state of the membrane lipids, or it may be affecting the carrier protein for the Ca*+ uptake system perhaps by modifying
Phosphate incorporation (% of control)
the
phosphorylation”3.‘23.
bl!muux-
100 Control 64” Taurine (20 mM) 2-Aminoethylhydrogen sulfate (20 mM) 60” 98 Guanidinoethanesulfonate (20 mM) 100 Isethionic acid (20 mM) 131” TAPS (2 mM) 128” TAHS (2 mM) 219” CAPS (20 mM) 85 CAHS (20 mM) 57” AEMS (20 mM) 60a ATS (20 mM) 56” APS (20 mM) 70” TMS (20 mM) 100 M-TMS (20 mM) “Indicates significant differences of individual compounds pared to the control value (P c: 0.05).
TAPS
com-
THQS
82.U K 66.2 TAU
K -
‘4-b
45.0 K ATS
PSA
31.0 K -
Fig. 3. Schematic interrelationships of ligand binding sites for taurine (TAU) and taurine analogues (see Figs. 1 and 2) on the retinal membrane in the ATF’-dependentCa’+ uptake system. Noncompetitive inhibition by TAPS or THQS toward taurine merely indicates that their binding site(s) are other than the taurine binding site. THQS and TAPS are synergistic, which suggests that THQS (or TAPS) may induce conformational changes that enhance the inhibitory binding of TAPS (or THQS). Similarly, PSA (a partial agonist) and taurine are synergistic and, thus, PSA may induce conformational changes on the binding site of tatnine and thereby enhance the stimulatory binding of taurine. Kinetic evaluation of the data for the combined usage of taurine plus ATS (an agonist) suggests an additive effect. The V,,, for taurine is equal in value to the V_ for ATS but is greater than the V,,, for PSA. (Reprinted from Ref. 133).
21.6 K -
-0
14.4 K -
CON TAU Fig. 4. SDS-polyacrylamide gel electrophoresis and autoradiography of phosphorylated membrane proteins obtained from a P , fraction of the rat retina. Arrows designated by a and b indicate bands of protein(s) with molecular masses of = 20 kDa and = 46 kDa (Reprinted from Ref. 123).
162
A third possible function for taurine in the retina is as a regulator of signal transduction due to its effects on protein phosphorylation. It is now well established that phosphoproteins along with necessary protein kinases and/or protein phosphata~s are enriched in the nerve terminal and thus synaptic transmission may be modulated or regulated by phosphorylation processes. In this context it has been shown that taurine has an inhibitory effect on protein phosphorylation (Table III) as demonstrated by the reduced amount of incorporation of radioactive phosphate into TCA precipitates of the rat retinal preparation’12*1’3’123Y1m. In addition, taurine has no effect on retinal phosphatase activity, thus supporting the concept that it is directly affecting a kinase systemr”. It has also been demonstrated in rat retinal homogenates that taurine (20 mM) has a specific inhibitory effect on a number of proteins with molecular mass rang ing from 20 kDa to 46 kDa. However, in a retinal P, fraction, a major band of proteins with a molecular mass of approximately 20 kDa (Fig. 4) appears to be most affected”2”23~1”. Similar experiments utilizing subcellular fractions of the rat heart and rat cortex have also demonstrated that taurine has an inhibitory effect on the phosphorylation of specific proteins 1os-110~129+2*7. An inverse relationship was generally observed in the rat retina between the structnral analogues of taurine that have been shown to be stimulators of Ca2+ uptake and inhibitors of protein phosphorylation and vice versa. Analogues that were shown to be inactive in the ATPdependent Ca2+ uptake system were also inactive in the protein phosphorylation system (compare data presented in Tables I and II with data in Table III). These observations thus suggested a causal relationship between protein phospho~lation and Ca2+ uptake. However, the precise nature of this relationship and the involvement of taurine in the visual process remains to be elucidated. The implication of the involvement of taurine with both Ca2+ fluxes and phosphorylation suggests a role for taurine in signal transduction in the retina. Tbese relationships should be investigated in parallel experiments involving the purification of both systems. The isolation of specific proteins involved in both the tau~ne-in~uenced Ca2+ uptake and protein phosphorylation reactions and the potential regulatory effects of taurine on these systems should be further explored in order to define the function of taurine in the retina.
REFERENCES 1 Adler, R., Taurine uptake by chick embryo r&inaI neurons and glial cells in purified culture, 1. Neurosci. Res., 10 (1983) 369-379.
In the last few years exciting observations have been made concerning the potential functions of taurine in the retina although an underlying mechanism for the actions of taurine at the molecular level remains to be defined. This information suggests specific roles for taurine in the retina of various species inclu~ng the possibility that taurine is a conditionally essential amino acid in the human species and thus negates earlier suggestions that taurine is a dead-end metabolite of methionine metabolism. This review has presented a number of possible functions for taurine in the retina. It now remains to prove or disprove the various hypotheses that have been put forth. 11. SUMMARY
The status and potential functions of taurine in the retina have been reviewed. Taurine is present in high ~n~ntrations in the retina of all species tested, while the retinal concentrations of the enzymes necessary to synthesize taurine are presumed to vary among those species. The documented low activity of ~ysteinesulfinic acid decarboxylase, a key enzyme in taurine biosynthesis, in the livers of the cat, monkey and human possibly reflect low activity in their retinas, indicating reliance on the diet as an important source of taurine. Both highand low-amity binding proteins and uptake systems have been described for taurine in retinal tissue. Evoked release of taurine by light and other depolarizing stimuli have been well documented. Retinal pathologies including diminished ERGS and morphologic changes have been reported for animals and man deficient in taurine. Possible functions for taurine in the retina include: (1) protection of the photoreceptor - based on the shielding effects of taurine on rod outer segments exposed to light and chemicals; (2), regulation of Ca2+ transport - based on the modulatory effects of taurine on Ca2+ fluxes in the presence and absence of ATP; and (3) regulation of signal transduction - based on the inhibitory effects of taurine on protein phosphorylation.
Acktwwledgtments. The author wishes to thank Mrs. Josie L. Aleman and Mrs. Mary Alba for typing the mmuscript and Mr. Douglas Taylor for performing the photography. Preparation of the manuscript and the author’s experiments were supported by NIH Grant EYO4780.
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163
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Brain Research Reviews, 16 (1991) 151-169 @ 1991 Elsevier science Pubhshers B.V. Ah rights reserved. 01~~173~~3.~ ADONIS 01~1~9~~1~ BRESR 90128
Taurine: retinal function John B. Lombardini ~e~~~
of Pharmacology and ~~h~~olo~
d Vimal Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430 (U.S.A.) (Accepted 9 April 1991)
Key wor&: Taurine; Retinal function; Uptake system; Binding protein; Electroretinogram; Taurine deficiency; Retinal degeneration; Regulator of ionic transport; Inhibitor of protein phosphorylation
CONTENTS 1. Jntroduction
.........................................................................................................................................................
151
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152
2. Taurine leveh
3. Synthetic enzymes
153
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4. Taurine binding proteins 5. Taurine uptake systems
.........................................................................................................................................
154
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6. Release mechanisms for tam-me ............................................................................................................................... 7. Effects of taurine on the electroretinogram
...............................................................................................................................................
9. Retinal degeneration
in animal models and humans due to taurine deficiency
154 155
................................................................................................................
8. Retinitis pigmentosa
153
156
..................................................................
156
10. Possible functions of taurine .................................................................................................................................... ....................................................................................................................... 10.1. Rote&ion of the photoreceptor 10.2. Regulation of CaZf transport .......................................................................................................................... ..................................................................................................................... 10.3. Regulation of signal infusion
157 157 158 162
11. summary
162
.............................................................................................................................................................
Acknowledgements References
162
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.................................................................................................................................................................
1. JNTRODUCMON
Taurine (2-~~th~esu~o~c acid) is a /krnino sulfonic acid that is present in milhmolar inundations in the animal kingdom but usually reported to be absent in the plant kingdoms” except for a few references to its presence in fungi3’ and pollenI&. However, Lahdesmlki observed millimolar concentrations of taurine in green leaves, seeds, fruit, and tubers of various plant species94. The initial discovery249and isolationN of taurine in 1827 and 1838, respectively, occurred in ox bile, and thus the derivation of the name from Taurus the Bull. Taurine is Correspondence: J.B. Lombardini, U.S.A. Fax: (1) (806) 743-2744.
Department
of ~~a~io~,
163
present in high concentrations in all animal tissues but it is in mammalian systems that the study of taurine generates perhaps its greatest interest due to its wide spectrum of biological activities in various tissues. The many possible functions of taurine include the following gamut: (a) ne~otr~s~tter (or neurom~ulator) in the CNS”; (b) stabilizer of biological membranes in many tissues” which affects cardiovascular functionsss’218and protects lymphoblastoid cells19*and spermatozoa6 against loss of activity; (c) protector of rod outer segments (ROSS) from exposure to toxic levels of light and chemicals165* t81; (d) modulator of calcium binding and fluxes75,133,169; Texas Tech University Health sciences Center,
Lubbock, TX 79430,
152 and (e) inhibitor of protein phospho~lation10~110,1’3~~23~ 129
The various studies on taurine reveal a major problem (or perhaps strength) due to the fact that more than one animal species has been investigated with respect to the possible functions of taurine. Many properties of taurine differ among various animal models which have been studied, including man. For example, in terms of taurine synthesis the adult rat is clearly capable of synthesizing su~~ent quantities of taurine to maintain total body levels73*238while the cat, monkey, and man must depend upon an exogenous source of taurine, i.e. the diet47,48,55,87,239,243. While this review is restricted to taurine and the retina, it still suffers limitations in formulating a role for taurine because of the difficulty in summarizing investigations which utilized many different animal species. Unfortunately, from individual data, one could devise a composite role for taurine in the retina which does not apply specificically to any particular species. In 1968 the first ~mprehensive review of taurine was published by Jacobsen and Smithss and since 1975 a series of international symposia have been held to discuss the biochemistry, physiology and pharmacology of taurine. Interest in the function of taurine over the last two decades has been considerable as suggested by the numerous review articles and monographs devoted to this compound 14,29,30,66,67,69,71,74,79,91,161.165,185,210,219,239.265 2. TAURINE LEVELS
Several lines of evidence suggest that taurine has a role in retinal function. The retina contains an extremely high amount of taurine and in some animal species the taurine levels in the retina are the highest of any tissue26* 33,~,50,51,60,83,89.141,143,177,237,261,269
-l-wo
nota,,je
excep_
tions of tissues with higher taurine levels are the neurohypophysis and pineal gland of the rat35. In the rat retina, taurine is the most abundant free amino acid comprising more than 50% of the total amino acid Depending upon the species the taurine pool 6o,143*177. content ranges from 10 pmol/g wet wt. in the frog retina to 50 and 52 pmol/g wet wt. in the rat and rabit retina with an intermediate value of 24 pmol/g wet wt. for the human retinaZ1. Within the retina taurine appears to be unevenly distributed and is concentrated in the photorereaching levels as high as 79 mM ceptor layerS4,150*“63*260 in the rat260V261. Immunocytochemical techniques have also been utilized to localize taurine in the rat, cat and guinea pig retina’@‘@‘. High levels of immunostaining reflecting the presence of taurine were observed in photoreceptor inner segments and synaptic terminals. Also amacrine and
bipolar cell bodies including their synaptic processes in the inner plexiform layer were high in taurine content. However, the pigment epithelium and distal parts of glial cells had only low levels of immunostaining. Recently, it has been demonstrated that there are differences between the immature (14-day old) and mature (12-week) rat in the location of taurine-like immunoreactivity in the retina93. In the retina of the immature rat, taurine-like immunoreacti~ty was observed primarily in the outerplexiform layer with onIy weak reactivity in the photoreceptor cell layer. However, in the mature rat, the cellular location of taurine-like immunoreactivity was found to be the opposite, i.e., present mainly in the inner segments of the photoreceptor cell layer but only weak reactivity observed in the outer plexiform layer. Localization of taurine-like immunoreactivity in the retina of the canary is similar to the immature rat in that the most intense reactivity is in the outer plexiform layerg3. However, taurine-like immunoreactivity was also observed in the photoreceptor cell layer, inner nuclear layer, and weakly in the ganglionic cell layer. The taurine content of the retina changes with age in some species. In the retina of the mouse taurine levels increase dramatically between day 12 and 16 (120 -+ 180 pmol/g dry retina) just after the eyes open6i. In the rat similar postnatal increases in retinal taurine content are observed and reach a maximum at approximately day 30 (Ref. 143). The taurine levels then decrease between 3 and 6 months of age in the rat16’17. Sturman and colleagues244 refer to their unpublished observations that retinal taurine content also increases in the gerbil and cat during development. In the chick retina, the observations reported in the literature are conflicting. Gupta and Mathurso report that taurine levels increase in the embryonic period if calculated on a wet weight basis but remain constant if based on protein”. After the chick hatches the taurine levels increase to a maximum at approximately day 14 (based on protein) and then decrease5’. However, Pasantes-Morales and colleagues’78 report that during incubation prior to hatching the taurine content (based on wet weight) of the chick retina decreases from day ll20. After hatching the taurine levels of the chicken retina increase based on wet weight (posthatching: day 1, 7.33 pmol/g; day 7,7.79 PmoYg; day 30,8.39 PmoVg and adult, 8.91 pmol/g)i7* (and also based on protein, personal communication with Pasantes-Morales). Taurine levels measured in the retinas from 6-day-old chickens reared in the dark were found to be approximately 90% greater than in the retinas of animals exposed to either constant light or a normal day-night cycle’78. Also, at day 3 the incorporation of [35S]taurine
153 into retinas of chickens reared in the dark was greater than in the animals exposed to a normal day/night cycle’78. Prior to day 3 the taurine levels were similar under the two conditions of light and darkness. It was suggested that light increases the release of taurine’78. No changes in the content of taurine in the monkey retina are reported for the time period from late gestation to maturity244. 3. SYNTHETIC ENZYMES
Initially the enzymatic synthesis of taurine produced much confusion and controversy due to a number of possible synthetic routes proposed for mammalian tissuessO. However, it is now considered that the primary pathway for synthesis is mediated through cysteinesulfinic acid (CSA) and thus a specific decarboxylation reaction is required to produce hypotaurine which is then converted to taurine. In the chicken, ox, and rat retina it has been established that taurine synthesis definitely occurs and that cysteinesulfinic acid decarboxylase (CSAD) is a key emyme59,142,147,213~ It has also been demonstrated that CSAD activity is regulated by the presence of light. CSAD activity and taurine levels are reduced in the light-adapted frog retina while increased in the darkadapted retina 76P92V159,160. Antibodies to CSAD have been produced and CSAD immunoreactivity is found in photoreceptor cells (both rods and cones) and bipolar, amacrine and ganglion cells in the rat retina’18 while in the rabbit retina the greatest CSAD immunoreactivity is located in the inner nuclear layer and the ganglion cell layer1’7V268.Compared to the rat, the human, monkey, and cat have much reduced CSAD activity in their livers (relative activity: rat 100, human 0.07, monkey 1, cat 1 (Ref. 47)) and it can be presumed that the levels of CSAD in the retina are similarly reduced or not present. Definitive measurements of CSAD activity in at least these 3 species have yet to be obtained for the retina. Also of interest is the observation that in the brain of several species (including rabbit, rat, monkey and human) the levels of taurine decrease with age either during fetal development or immediately after birth whereas at least in the rat brain the activity of CSAD is reported to increase with age2*‘79*“’ although these data should be viewed with caution (see below). This inverse relationship between taurine levels and CSAD activity in the brain is not observed in the retina of the rat. As discussed above, taurine levels in the rat retina increase with age up to day 30 (Ref. 143). CSAD activity in the rat retina also increases with age-approximately 3-fold between 10 and 30 day8 after birth’82. Taurine levels within the various tissues of the eye, however, do not appear to correlate with CSAD activ-
ity 59. While the retina has the highest content of taurine compared to the lens, iris-cillary body or cornea, the cornea contains the highest activity of CSAD. Heinlmslki 59 thus suggests that an intraocular transport mechanism may be involved in the regulation of taurine levels within the various ocular tissues. It should be pointed out that some of the CSAD and taurine assays have been fraught with error due to methodological difficulties. First, the CSAD assay has been questioned especially in the older literature because CSA is also decarboxylated by glutamate decarboxylase depending upon the substrate concentration (reviewed in Ref. 68). For instance, concentrations of lo-48 mM CSA were used to measure CSAD activity in the rat brain2,1W and ocular tissues59*‘82.However, the levels of CSA in various regions of the rat brain have been determined to be in the range of 0.01-0.29 mM (reviewed in Ref. 68). Thus, assaying for CSAD in the presence of CSA at one or more of magnitidue higher than its physiologic substrate concentration may yield spurious results due to the observation that glutamate decarboxylase may also decarboxylate CSA when CSA is added to the incubation system at such a high concentration. The resolution as to whether CSAD correlates or does not correlate with taurine levels in brain, ocular or any other tissue must be reevaluated by utilizing proper enzymatic methodologies. Second, ninhydrin positive materials (e.g. glycerophosphoethanolamines) that may co-migrate with taurine on the amino acid analyzer can yield falsely elevated taurine levels in tissue samples52*248. Other enzymes involved in the synthesis of taurine and reported to be present in the retina (of at least some species) are cysteine dioxygenase (cysteine oxidase) which catalyzes the conversion of cysteine to cysteinesultjnate42J42J83 and hypotaurine dehydrogenase which oxidizes hypotaurine to taurine41 possibly through a disulfone intermediate45. Cysteine dioxygenase has been demonstrated to be primarily localized to the inner segments and photoreceptors in the ox retina but appears to be absent in the ROSS’~~. 4. TAURINE BINDING PROTEINS
Further evidence of a role for taurine in the retina is the presence of two binding proteins specific for taurine. The two binding sites (high-affinity site, 7 PM; low-affinity site, 330 PM) demonstrated in the rat are sodiumdependent and are thus perhaps involved with taurine uptake sites’“. It is suggested due to the similarities between taurine binding and taurine transport, i.e. sodium dependence and approximate agreement between transport and binding constants, that the binding processes observed in the rat retina are associated with transport
154 systems for taurine’34. This conclusion is supported by the earlier observations of Ldpez-Colomt? and PasantesMorales’38 who observed in a chick retinal membrane preparation a highly Na+-dependent dissociation constant of 9.32 ,uM, a value which is in the same order of magnitude for the K,,, kinetic constants for the high-affinity uptake system for taurine transport in brain slices”* 12’ and synaptosomes62*95’221. Mpez-Colomt and Pasantes-Morales 13’also measured [3H]taurine binding in the absence of Na+. This binding is extremely low. Arguments are presented which rule out the interpretation that the observed Na+-independent [3H]taurine binding is an interaction with postsynaptic receptor sites in the chick retina. In other experiments by Salceda and Pasantes-Morales2r5, a single binding site for taurine with a dissociation constant of 98 ,uM was demonstrated in the rat retina when Na+ was omitted from the incubation medium. Again this Na+independent taurine binding demonstrates properties different from those generally attributed to postsynaptic binding to receptors such as has been observed for the amino acid neurotransmitters glycine, glutamate and y-aminobutyric acid. Evidence has also been reported that taurine interacts with [3H]strychnine binding sites in the rat2r6 and bovine25 retina. Taurine is equipotent with glycine in inhibiting high-affinity, low-capacity [3H]strychnine binding to retinal membranes in the rat216 but has less effect than glycine in the bovine retina25. Schaeffer and Anderson2r6 have suggested that taurine may have a specific binding site in the rat retina and/or may interact with glycine binding sites.
It has also been demonstrated tht metabolic inhibitors and temperature greatly influence the uptake of taurine in the retina212. Addition of either 2,4_dinitrophenol or ouabain significantly reduces taurine uptake as does lowering the incubation temperature to 4 “C. Observations that taurine increases (in a sodium-dependent fashion) the ouabain-sensitive apical Na+K+ pump in retinal pigment epithelium were recently reported220. In these electrophysiologic studies it was also demonstrated that taurine inhibits the apical positive transepithelial potential in the bullfrog retina. These studies thus suggest that taurine is directly involved in an electrogenic sodium/taurine cotransport mechanism. The distribution of radioactive taurine taken up by the retina has been studied by autoradiographic techniques. In the mouse retina, [35S]taurine accumulated, after either intravitreal or intravascular injection, in the outer nuclear layer, the inner nuclear layer, and the Mtiller cell processes20c while in the newt retina, amacrine cells found within the ganglion cell layer accumulated [35H]taurine’2. In the rat and cat, autoradiography showed the accumulation of [3H]taurine in Mtiller, photoreceptor, and amacrine cells201,234. 6. RELEASE MECHANISMS
FOR TAURINE
Perhaps the first identification of a function for taurine was in the chick retina where it was observed that depolarizing agents and light stimulate the release of radioactive taurine and thus it was suggested that taurine may be involved in the mechanism of light excitation and/or dark adaptation’79Y194’1W. Flashes of light have also been shown to release endogenous taurine from the rabbit retina151*‘53. 5. TAURINE UPTAKE SYSTEMS The site of the release of taurine has been identified as the rod outer segments (ROSS) in the frog retina214 Along with the high-affinity binding site for taurine and by indirect evidence as the photoreceptor layer of there are also numerous studies demonstrating the the chick retina1ss*211.Additional evidence that taurine presence of a high-afhnity transport system for taurine has a role in the photoreceptors was demonstrated by in the retina and pigment epithelium of the rat, toad, frog, chick, cat, rabbit, baboon, and human39Y44,46*61s5Y Schmidt222 who observed that the light-evoked release of 105,106,152,212,215.223,224,227,228,234-236 taurine is present in isolated cat and rat retinas but is . High-affinity transabsent in the photoreceptorless retina of the Royal Colport has also been demonstrated in chick embryo retinal lege of Surgeons (RCS) rat. Thus, with the above obneurons, glial cells and retinoblastoma cells in culturel’ servations plus the depressant effect of taurine on reti1W*270*271. A low-affinity taurine transport system and/or nal neuronal activity36*86,170,it has been suggested that a non-saturable uptake mechanism has been reported for certain of the above animal species39,152,212,227,u4Y235, taurine may be an inhibitory neurotransmitter 144*145*202 although there is evidence to the contrary15*. For exam270*271.However, the presence of two transport sysple, while high potassium and the ionophore A23187 terns appears to depend upon the age and the species evoke the release of radioactive taurine from whole chick studied. For instance, Salceda2i2 has shown that the retina, the release of taurine from a synaptosomal fracadult rat and the 15-day embryo chick have two transtion was unaffected by these agents’39*188.Veratridine port systems for taurine while the 20- and 30-day-old rat also had no effect on releasing taurine from subcellular and the adult chick have only the low-affinity transport retinal fractionsls8. Thus, in these studies it was consystem.
155 eluded that taut&e was not being released from nerve terminals and hence is not a neurotransmitter139’1ss. Other effecters of taurine release from the retina are the calcium ionophore X537A’93 and electrical stimulation 224. However, it appears that electrical stimulation of taurine release may be due to non-specific tissue damageu3. Also, when taurine release is compared to the release of the putative amino acid n~uro~ans~~ers, there are significant differences such as: (a) light stimulates the release of taurine from the whole chick retina but has no effect on GABA, glutamate, or glycine release’“; (b) colchicine inhibits the stimulated release of taurine by potassium, veratridine, and glutamate in the chick retina but has no effect on GABA release’95; and (c) cytochalasin B has a significant effect on the glutamateand veratridine-stimulated release of taurine but only a slight effect on GABA releaselp5. The potassium-stimulated release of [3H]taurine from the rat retina is only partially calcium-dependent (contrary to j3H]glycine release which was tested in the same tissue preparation)uJ and occurs only after the stimulus (IL’) is removed from the superfusing medium, i.e. a slow delayed release=’ 176,235.Dopamine also affects both the spontaneous and K-evoked release of [3H]taurine from the superfused rat retina203. When dopamine and K+ are added simultaneously to the isolated retina the delayed release of taurine is not affected, However, the delayed release of taurine can be effectively blocked if dopamine is added to the predation after the K+-stimulus. Effecters such as glutamate, aspartic, cysteic acid, kainic acid and N-methylaspartate which stimulate release of radioactive GABA an&or glycine have no effect on taurine release from isolated, perfused chick retinala. These results suggest that taurine release is occurring through a different mechanism(s) than the one accepted for the classic neurotransmitters and thus tend to diminish the possibility that taurine is a neuro~ans~~er in the photoreceptors. However, more recent studies in the rabbit retina suggest that taurine may be a neurotransmitter in amacrine cellist’. Alternatively, it has been suggested that taurine may be involved in the contractile processes of the photoreceptors due to the inhibition of the light-stimulated release of radioactive taurine by colchicine, vinblastine, and cytochalasin B which are known to interfere with contractile eventslm. Finally, recent studies demonstrate that the release of radioactive taurine from chick retinas occurs through two mechanisms43*‘76. The minor component of the release mechanism is calcium-dependent and related to membrane depolarixation, while the major component is chloride-dependent and calcium-independent and also dependent upon an increase in cell volume43T176.It is
postulated that two different cell types or in~a~~~ar pools may be involved with taurine release from the retina. Pasantes-Morales and her colleagues have thus concluded that changes in ceil volume are responsible for the taurine released when retinal preparations are exposed to high K+ inundations. Therefore, the release of taurine is not due to an event brought about by K+evoked depolarization. In their experiments, if depolarization was causing ]3H]taurine release then the absence or reduction of Cl- in the medium should have increased depolarization with a subsequent increase in [3H]taurine release which was not observediW. Not only is taurine released from the retina under a variety of conditions, but taurine itself also affects the release of the neurotransmitter acetylcholine38. It has been demonstrated in the rabbit retina that the lightevoked release of acetylcholine from bipolar cells and/or amacrine cells is abolished by 1 mM taurine. However, the spontaneous release of acetylcholine was not affected by taurine. Strychnine blocked the effects of taurine. It was concluded from these studies that choline@ activity in amacrine cells in the rabbit retina may be influenced by taurine. 7. EFFEXTS OF TAURINE
ON THE ELECTROREZTINO-
GRAM
In the 1970’s when taurine was first proposed to be an inhibitory neurotransmitter in the retina a number of studies were conducted which measured the effects of taurine on the electroretinogram (ERG). Physiologic doses of taurine depress the b-wave of the ERG in the chicken and frog retina9’23’131’170’1%‘252’253 but are without effect on the a-wavew~170V196~2J2. The effects of taurine on the ERG are antagonized by strychnine but unaffected by picrotoxin which stands in exact contrast to those effects for GABA and led to the postulation that tam-me may be exerting its effects ~sts~aptica~y~. Intracellular recordings from the mudpuppy and frog retina have demonstrated that ganglion cells are sensitive to taurine and taurine may be involved in the OFF response of ganglion cells”“‘. It has also been demonstrated by intracellular recordings that taurine and glytine are equally effective in inhibiting spike activity in turtle and cat ganglion cells’0,22. However, in electrophysiolo~c studies involving the cat retina a tr~smitter role for glycine in the inner retina was favored over taurine because of the presence of a transport system for [3H]glycine and localisation of [3H]glycine in amatine cells. Similar results were not obtained for taurine**. Finally, it has been recently suggested by electrophysiological and morphological experiments that tau-
156
rine has a protective effect against hypoxia in the retinam. Taurine (1 mM) produced a significant recovery in the b-wave amplitude in dark-adapted, perfused bovine eyes after exposure to hypoxic conditions. In addition, the mitochondrial damage that was observed in the inner segment of the photoreceptors after an ischemic/ hypoxic episode was reduced after treatment with taurine (1 mM). 8. RETINITIS PIGM~~OSA
The late Dr. And& Barbeau, who had a keen interest in determining the function of taurine, stated that, unless a disease is associated with taurine, interest in this sulfi~r amino acid will wane. Therefore, great hopes for taurine in preventing pathology were raised when it was observed that both the levels of taurine in platelets and plasma3~4*25fand taurine uptake in platelets395,ti were decreased in a subpopulation of patients with retinitis pigmentosa (RP). Blood levels of taurine were also demonstrated to be decreased in specific genetic subclasses of RP patients” although normal values were reported in earlier (in plasmam) and later studiesZ5. On the contrary, patients who expressed an autosomal dominant RP with both rods and cones equally disturbed (R-type) had elevated plasma taurine levels65. The evidence for the differences in the uptake of taurine in the RP patients compared to controls has also been shown to be in~ns~tent. Voaden and colleagues2J6 found no difference in taurine uptake in platelets of simplex and autosomal dominant RP patients in contrast to Airaksiuen et al.3, but found that the capacity of the high-affinity transport system was higher in patients with X-linked hemizygote and multiplex disea#‘. Whether these are indeed changes in taurine uptake or changes in blood homeostasis of the RP patient remains to be clarified”‘. However, even with the confusion relating to the value of taurine measurements in RP patients, taurine supplementation has been utilized in an attempt to improve the clinical situation’@. Unfortunately, taurine supplementation of l-2 g/day for one year in RP patients did not produce any si~fi~nt clinical change. A different approach utilizing lymphoblastoid cells which possess a hip-affinity uptake system for taurine has been used to potentially monitor RP patients2665267. It was demonstrated that l~phobl~toid cells from RP patients differ from control cell lines in their ability to take up taurine266. The V,,,, for taurine uptake in cell lines from RP patients is lower while the K, is greater than values obtained for control cell lines. Finally, the question was posed whether urinary taurine can be used as a marker for RF’18.The answer is: no. Dr. Barbeau would have been disappointed.
9. RETINAL DEGENERATION
IN ANIMAL MODELS AND
HUMANS DUE TO TAURINE DEFICIENCY
Animal models of hereditary retinal degenerations have been studied for their retinal taurine content. However, it is concluded that in rd mice, RCS rats, and Irish setter dogs with rod-cone dysplasia the loss of taurine in the retina is secondary to the loss of photore~ptor cells’62*22s9227. In the Abyssinian cat with dominant rodcone dysplasia there appears to be no abno~~ity in taurine uptake or levels in the pigment epithelium compared to controls257. While the data are controversial regarding the relationship between taurine and RF’ there is no doubt that retinal pathology can be induced in animal models by a dietary taurine deficiency. The first report of retinal degeneration associated with a taurine deficiency was by Hayes and colleagues56 who demonstrated that both in the kitten and adult cat a central retinal degeneration appears after 3 months of diets lacking in taurine. Their results provided the stimulation for research which ultimately generated evidence that dietary taurine is necessary for the human species. This evidence, although not proven, prompted infant formula manufactures in the U.S.A. and abroad to add taurine to their synthetic diets. Numerous studies have been performed with the cat as an animal model for taurine deficiency and all are in basic agreement that taurine is an essential component of the diet, and that its absence leads to severe retinal damage involving the outer segments of the photoreceptors and the tapetum 8,15,19,2?,57,?8,175.226,229,230,240,242,245, a7*262$263. Specifically, the damage manifests itself in severe disorganization and in a reduction in thickness of these areas; the disk membranes also demonstrate disorientation plus vesiculation and swelling. The tapetal cells in the taurine-deficient cat contain electron-dense globules and appear either shrunken or swollen depending upon their location either in the inner or outer layers. In casein-fed cats which subsequently become taurine deficient the amplitude of the b-wave of the ERG is reduced and the cone b-wave implicit times are delayed81* 82,u)6_In other studies the ~plitude of the a-wave was also reduced21~78~8*~82~175,206, Loss of rhodopsin in certain regions, specifically the horizontal streak area extending from the central retina to the nasal retina which normally contains high rhodopsin content, have been observed in the taurine-deficient catsl. In the infant rhesus monkey taurine deficiency produced by feeding a taurine-free or low-taurine infant formula also produces retinal abnormalities, specifically, a diminution of the cone ERG and degeneration of the
157 ultrastructure of the cone photoreceptors resulting in loss of visual acuity”,154-157,246.However, when placed on a diet deficient in taurine infant ccbus and cynomolgus monkeys appear to conserve taurine to a greater extent than the cat and while growth was depressed retinal degeneration was not observed5*. Taurine deficiency is more difficult to produce in the rat, since this animal is capable of synthesizing taurine in sufficient quantities from endogenous precursors and thus a taurine-deficient diet has no observable effect. However, the taurine analogue and transport inhibitor, guanidinoethanesulfonic acid (GES), when placed in the drinking water rapidly (- 2-3 weeks) depletes the body stores of taurine in the rat63,72. When the rat is treated with GES, high-affinity taurine uptake into the retina is competitively inhibited’0’*2a“ and the retinal levels of taurine are diminished to approximately 30-40% of control values%,g,2as. pups of nursing mothers treated with GES have retinal levels of taurine 50-70% of controls9*. Retinal pathologies including both changes in the ERG and alterations in morphology are also observed in the albino rat when the taurine levels are decreased with GES treatment. Changes in the ERG include decreases in amplitude of the a- and b-wave32,53*99,2059207 while damage to the photoreceptors includes a reduction in the size of the layer, disarray of the disks and disk membranes, swollen inner segments and nuclei, and accumulation of vesicular membrane-bound profiles within the basal region of both rods and cones53,104,191*un, These abnormalities frequently lead to cell death. In the albino rat, the pigment epithelial cells were shown to be damaged by taurine depletion. In the cat, however, no changes (or less severe changes) were observed in this tissue (Ref. 57; also discussed in Ref. 104). While it is well documented that taurine depletion produces morphologic changes, such as photoreceptor cell loss, in the retina of the albino rat, similar changes are not observed in the retina of the pigmented rat although a reduction in ERG amplitudes does occurm. Thus, it is suggested that in the albino rat light may increase the degenerative changes induced by taurine depletion 102*104,u)5*208, 231.The effects of taurine depletion on the ERG, retinal structure, and the interactions between taurine deficiency and ambient lighting are reviewed by Lake”“‘. /?-Alanine, also a taurine transport inhibitor, when injected intraperitoneally into adult rats produced disruption of the photoreceptor structure”’ but had no significant effects on taurine levels in the retinalo3. The above background material leads to the question how taurine deficiency affects human vision. The evidence is somewhat scanty and not definitive. However, infants and children fed totally by parenteral nutrition which was lacking in taurine developed low plasma tau-
rine levels accompanied by reduced amplitudes in the ERG and morphologic changes observed by ophthahnosThese abnormalities were corrected in 7,48,49*254. COPY some of the children when taurine was added to the infusate. It is thus suggested that taurine is a conditionally essential amino acid in very specific nutritional circumstances such as total parenteral nutrition. The obvious but unanswered question is why all the abnormalities in the children were not corrected. Contrary results as to the benefit of taurine supplementation have also recently been published13. In these experiments, taurine supplementation (0.4% in diet) was visual function found to cause additional deterioration rotein enas monitored by ERGS in rats which wer ergy malnourished. Taurine supplementati n did not have any adverse effects in control rats or rats which “:: at the above were pair-fed. It was concluded that tauri dietary level is conditionally toxic in low protein diets. Thus, these investigators suggested that the status of the patient relative to his/her ability to regulate taurine in diseased or malnourished tissues be assessed prior to taurine supplementation. Finally, in considering taurine as a conditionally essential nutrient as previously discussed, Lima and colleagues”5*“6 have demonstrated that taurine has a stimulatory effect on the outgrowth of retinal explants in goldfish. The effect of taurine is concentration dependent at low concentrations (l-4 mM) but becomes inhibitory to explant regeneration at high concentrations. The time relationships between addition of taurine and growth of the explants suggest that there is a critical period for taurine to be effective. However, the mechanism for the effect of taurine on explant regeneration is unknown, 10. POSSIBLE FUNGI-IONS OF TAURINE
In recent years taurine function in the retina has centered around 3 possibilities: (1) protection of the photoreceptor-based on the shielding effects of taurine on ROSS exposed to light and chemicals; (2) regulation of Ca2+ transport-based on the modulatory effects of taurine on Ca2+ fluxes in the presence and absence of ATF; and (3) regulation of signal transduction-based on the inhibitory effects of taurine on protein phosphorylation. 10.1 Protection of the photoreceptor Exposure of isolated ROSS obtained from frogs to either continuous illumination or chemicals such as ferrous sulfate produces gross morphological changes evidenced by severe disruption of the structure characterized by swelling and vesiculation. In isolated frog ROS preparations taurine decreases light-induced damage in a dose-
158 dependent
(5-25 mM) fashion168*171*173.Twenty-five
taurine lowers the percentage ues lower than those normally controls.
Other amino acids such as glycine and GABA
had a similar present
protective
effect but, since they are not
in high concentrations
in the ROSS, this physi-
ologic role was not attributed protects
mM
of disrupted ROS to valobserved in dark-adapted
the ROSS against
to thernla.
disruption
but only if 100 PM zinc is present; in the absence
by ferrous
taurine
also
sulfate
has no effect
of zinc171V173.
Both light and ferrous lipid peroxidation
cause an increase
by malonaldehyde
involving
by taurine174. ferrous
sulfate
in
forma-
frog ROSS. The light-induced
is not affected
the experiments
sulfate
as measured
tion in the isolated peroxidation
Taurine
However,
lipid in
the increased
the
incubation
system.
At
high
Ca*+
concentrations
(1.4-2.5 mM) taurine is inhibitory in the chick, frog, and rat113.13*.13’,1~,16’,169,171while at low ca2+ concentra_ tions (10-100 PM) and in the presence stimulatory
of ATP taurine
Presently, there is only speculation as to the physiologic meaning of the biphasic effects of taurine on Ca*+ fluxes in the ROS. Assuming visual transduction
that Ca*+ has a role in the
process it has been suggested that the
taurine-stimulated uptake of Ca*+ into disks is a means to remove Ca*+ from the cytoplasm”‘. A similar argument for the role of taurine also been
in the nerve
taurine
could perhaps
terminate
Ca*+-dependent
It is speculated that the protective effect of taurine on isolated frog retinal membrane structures against peroxidation-induced damage is due to its interactions with ion permeability and/or water accumulation in the membranes 171~174~192 and not due to any effects on membrane
dria) by a process which is energy dependent
10.2. Regulation of Ca2+ transport A second possible function for taurine in the retina is It has been demonthat it regulates Ca*+ transport. strated that taurine has a biphasic effect on Ca*+ accumulation depending upon the concentration of Ca*+ in
has
Ca*+ uptake into mitochondria located within the nerve terminals which is stimulated by transmitter
regulating ionic fluxes it has been suggested that taurine may reduce the oxidative and peroxidative products produced in the retina and thus attenuate their damage and/or prevent cell death%‘. One of these products is hypocholorous acid which is effectively neutralized by taurine119’264.
terminal
proposed169.
lipid peroxidation was also accompanied by water accumulation which was decreased by taurinel’*.
fluidity 149. Thus a function for taurine as an osmoregulator has been suggested. This conclusion is based partly on the observations that the light-induced damage in the ROSS requires the presence of bicarbonate, sodium, and chloride ions and possibly involves proton fluxes and regulation of the pH of the ROS. However, further complicating the possible mechanism for the protective effect of taurine is the observation that the addition of taurine prevents the disruption of ROSS in a calciumfree medium and modifies Ca*+ fluxes within these structures’a”71. These data thus suggest that Ca*+ and taurine are also intimately involved in a mechanism to maintain and stabilize the structural and functional integrity of the photoreceptor membranes. In rats light-induced ‘photoreceptor disruption and loss was not prevented by the administration of taurine (5%) in the drinking water 259. The protective effects of taurine on ROSS are summarized by Pasantes-Morales et al. 181. As a corollary to the possible function of taurine in
is
90,111,112,114,121-128,131,133,137,1W,169,171,187
removed
release’28~169. In either into a subcellular
organelle
neuro-
case Ca*+ is being (disk or mitochon(requiring
ATP) and stimulated by taurine. A functional role for the inhibitory effects of taurine on Ca*+ flux in the absence of ATP and at high Ca*+ concentrations (in the millimolar range) is more difficult to envision. It has been suggested that a calcium-calcium exchange process is occurring under these conditions without a net uptake of calcium137*161*232.However, the physiologic meaning of the inhibitory effect of taurine on this process remains to be clarified. When a series of taurine analogues were tested for their effects on 45Ca2f accumulation in a rat retinal preparation at high Ca*+ concentration (1.4 mM), it was determined that only taurine and a-sulfo-/l-alar&e are inhibitory13*. Addition of the calcium ionophore A23187 to the retinal system had no effect on 45Ca2+ accumulation which suggests that the 45Ca2+ accumulation was due to 45Ca2+ binding to membrane surface components rather than being transported into vesicular components of the retinal preparation13*. When A23187 was added to the retinal preparation in the presence of (*)trans-2aminocyclohexanesulfonic acid the accumulation of 45Ca was further increased by a factor of 2 beyond the stimulation observed with the cyclic taurine analogue alone, indicating that the cyclic taurine analogue might have altered Ca*+ binding sites within some vesicular entities. These modifications might have then allowed more Ca*+ to be bound within the vesicles when additional 45Ca2+ was made available by the membrane-disrupting properties of the ionophore A23187. The specificity of taurine in stimulating ATP-dependent Ca*+ uptake has been studied extensively. Numerous analogues of taurine of widely varying chemical structures have been used to determine the structural requirements for stimulating Ca*+ transport in the rat retina. Modifications of the sulfonic acid moiety of tau-
159 rine are well tolerated and close structural analogues of taurine such as hypotaurine, 2-aminoethanephosphonic acid, and Zaminoethylhydrogen sulfate are stimulators of ATP-dependent Ca2+ uptake’n’lu. Modifications of the amino moiety of taurine are less tolerated and thus isethionic acid and guanidinoethanesulfonic acid do not have any stimulatory activity121F’23.The taurine analogue with a 3 carbon backbone between the amino and sulfonic acid moieties is inactive122’126while aminomethanesulfonic acid is an inhibitorlz. Glycine and p-alanine are stimulators’22. Analogues of taurine have also been tested in frog ROSS for their effects on ATR-dependent Ca2+ uptake. Cysteinesuhinic acid and hypotaurine stimulated Ca2+ uptake although to a lesser extent than taurineW”64. Conflicting (stimulatory or no effect) data have been presented for /?-alanine and glutamic acid90*161Y187. Guanidinoethanesulfonic acid, GABA, glycine, histidine, and proline had little or no effect in the system which utihzed a frog ROS preparationW*1&1*‘87. Compounds which contain the taurine structure within a ring configuration and thus are conformationally more rigid than taurine have been tested for their effects on ATP-dependent Ca2+ uptake in rat retinal preparations 112V114.Four analogues have been synthesized: ( +)WWLS-and (*)&2-aminocyclohexanesulfonic acid (TAHS and CAHS), and (?)trans- and (+)c&Zaminocyclopentanesulfonic acid (TARS and CARS) (Fig. 1). CAHS was shown to be a stimulator of ATP-dependent Ca2+ uptake though not as potent as taurine while TAPS and TAHS were potent inhibitors with I,, values in the PM range (Table I). CARS was also an inhibitor though quite weak (Iso = 1.8 mM). These unanticipated results cannot be explained by the differences in the intraatomic distances between the nitrogen of the amino and the sulfur of the sulfonic acid moieties. The distances between the heteroatoms of TARS and TAHS was 4.0
A if the functional groups for the molecules are placed in an equatorial-equatorial conformation for TARS and in a diaxial orientation for TAHS (Fig. 1). In CAHS the intra-atomic distances were 3.0 and 3.1 A in either of the possible conformations (axial amino-equatorial sulfonate or equatorial amino-axial sulfonate). CARS was erroneously predicted to be a stimulator of ATF-dependent Ca2+ uptake based on an intra-atomic distance of 2.7 A for the heteroatoms rater than an inhibitor. Thus, it was suggested that the size of the alkyl moiety and its relative position in the molecule contributed to the differences in the biological activities112. A second series of taurine analogues in which the sulfonic acid moiety was replaced with a sulfone moiety was also synthesized and tested for activity in the ATP-dependent Ca2+ uptake system in rat retinal preparations”‘* ‘13 (Fig. 2). 2-Aminoethylmethylsulfone (ARMS), (&)3aminotetrahydrothiopyran-1, l-dioxide (AI’S), and( +)3aminotetrahydrothiophene- 1,l-dioxide (ATS) , compounds which contain a primary amine, were found to be more potent stimulators of Ca2+ uptake than taurine. However, two analogues, thiomorpholine-&l-dioxide (TMS) and N-methylthiomorpholine-l,l-dioxide (M-TMS), which do not contain a free amino moiety but
TABLE I Effects of taurine and cyclic taurine analogues on ATP-dependent Cd’ ion uptake by a rat retinal membrane preparation Data are presented as means f S.E.M. Means with different superscripts are significantly different (P < 0.05) from each other. (Reprinted from Ref. 112). Compound
Taurine TAPS CAPS TAHS CAHS
Concentration required for 50% inhibition (wW 39 f 5” (5) 1775 + 403b (4) 86 2 13’ (6) -
Concentration required for 50% stimulation (mW 8.1 + 1.4 (7) 6.; +- 3.2 (4)
Fig. 1. Structures of the diasteromeric racemates of 2-aminocyclohexane sulfonic acid and 2-aminocyclopentane sulfonic acid. ‘lkvo possible conformations are shown for each cyclic analogue. (Reprinted from Ref. 112).
160 the distinct possibility that the sulfones are exerting stimulatory effects through different mechanisms.
H3C-S 0
The effects of various taurine analogues in combination with taurine have also been tested in the ATP-de-
I
pendent
//\
0
mine
I-AMINOETHVLMETHVL SULFONE
N-METHVLTHIOUORPHOLlNE-
THDMORPHOLINE1.1~DIOXIDE
(AEM.
l.l-DIOXIDE
/
Ca2+ uptake system of the rat retina to deterrelationships and possible synergistic
kinetic
effects’31’133. TAPS (Fig. 1) and 1,2,3,4_tetrahydroquinoline-&sulfonic
acid (THQS),
uptake,
when tested
non-competitive
c
in combination
separately
of Ca”+
were determined
with respect to taurine were demonstrated
to be
and when tested
to be strongly
syner-
gistic. Kinetic data suggest that TAPS and THQS have a similar mode of action, i.e. mutually exclusive133. ATS
s03H
(Fig. 2) and (*)piperidine-3-sulfonic
TAURINE (TAU)
//\ 0
0
//\
0
PHENE-l.l-DIOXIDE
CAPS)
(ATS)
Fig. 2. Structures of taurine and sulfone analogues of taurine. (Reprinted from Ref. 113).
a secondary or tertiary amine placed structure, were inactive (Table II).
within
the ring
The findings that the sulfone analogues of taurine which contain primary amines (AEMS, APS and ATS) are potent stimulators of ATP-dependent Ca2+ uptake are of considerable interest, since sulfonic acids at physiologic conditions are ionized while sulfones are nonionized. Sulfonic acids and sulfones are not considered to be classical isosteric functional groups. Thus, there is
TABLE II Effects of taurine and sulfone analogues of tourine on ATPdependent Ca2+ uptake by a rat retinal membrane preparation
Data are presented as means + S.E.M. Taurine and analogues (see Fig. 2) were tested at a tinal concentration of 20 mM. Means with different superscripts are significantly different (P < 0.05) from each other. (Data are reprinted from Ref. 113). Compound
Cd’ uptake (nmollmg protein)
Control Taurine AEMS ATS APS TMS M-TMS
1.6 4.7 7.8 9.6 7.3 3.0 1.9
+ 2 2 2 f + +
0.2’ 0.4b 1.2c.d 1.3” 0.6d 0.Y.b 0.4”
an ag-
Ca2+ up-
take system,
exclusive
were also shown to be mutually However,
while the combi-
nation of taurine plus ATS is additive the combination of taurine plus PSA is synergistic. The relationships of the effects of these compounds on ATP-dependent Ca’+ uptake are shown in Fig. 3.
(t)3-AMINOTETRAHVDROTHIO-
PVRAN-l.l-DIOXIDE
acid (PSA),
onist and partial agonist in the ATP-dependent when tested in combination.
(~)~-A~~~NoTETRAHvDR~THIo-
a weak inhibitor
w-TMS)
CTMSLO
NH2
0
their
(19) (19) (6) (9) (3) (7) (4)
Taurine has an opposite effect, i.e. inhibitory rather than stimulatory, on Ca*+ accumulation when the Ca*+ concentrations are elevated to the mM (1.4-2.5 mM) range 113,132,137,166. At a concentration of lo-20 mM, taurine inhibits Ca*+ accumulation by 2575% depending upon the species and the retinal preparation. Various analogues of taurine have also been tested for their effects on ATP-independent Ca*+ accumulation at high (1.4-2.5 mM) concentrations of Ca*+. In frog ROSS 10 mM glycine, GABA, and p-alanine had no effect13’ while in various subcellular fractions of the chick retina 10 mM glycine and /3-alanine had a slight effect’&. In the chick GABA and glutamate had no activityl@. In the rat retina when tested at a concentration of 20 mM the sulfone analogues of taurine, AEMS, APS, and ATS (Fig. 2) - stimulators of ATP-dependent Ca*+ uptake - were more potent inhibitors of ATP-independent Ca*+ accumulation than taurine itself113. The sulfone analogue of taurine containing a secondary amine, TMS, also was inhibitory equipotent with taurine; however, the tertiary amine derivative, M-TMS, was inactive’13. TAPS and TAHS (Fig. 1) have been shown to be stimulators of ATP-independent Ca*+ accumulation at a high (1.4 mM) Ca*+ concentration132. This is directly opposite to the effect observed in the ATP-dependent Ca*+ uptake system at low (10 PM) Ca*+ concentration in which TAPS and TAHS were potent inhibitors”*~‘t4. CAPS and CAHS have no effect on Ca*+ accumulation at high Ca*+ concentrationt3*. The studies utilizing taurine and taurine analogues as modulators of Ca*+ uptake and/or accumulation demonstrate the specificity for the taurine structure in this phys-
161
iologic process.
In attempting
taurine
retina
in the
clearly emphasize
to define a function
structure-activity
for
relationships
the uniqueness
and importance of the
taurine structure in this tissue. It has also been demonstrated
in Arrhenius plots that
TABLE III Effect3 of taurine and taurine analogues on incorporation of radioactivephosphate into rat retinal membrane proteins TAPS and TAHS could not be tested at 20 mM due to lack of solubility in aqueous solutions. Structures of analogues are presented in Figs. 1 and 2. (Data compiled from Refs. 112, 113, 123).
taurine affects the transition temperature of ATP-dependent Ca*+ uptake in rat retinal membrane prepara-
~~
tions?*‘. Taurine (20 mM) elevates
Compound
perature
from
the transition
17.9” to 25.4 “C while
lowering
tem-
apparent activation energy for Ca2+ uptake. Interpretation of these results is only speculative tion is that taurine may be inducing change within the membrane.
but the implicaa conformational
Taurine may be causing a
change within the structure of the membrane by directly affecting the physical state of the membrane lipids, or it may be affecting the carrier protein for the Ca*+ uptake system perhaps by modifying
Phosphate incorporation (% of control)
the
phosphorylation”3.‘23.
bl!muux-
100 Control 64” Taurine (20 mM) 2-Aminoethylhydrogen sulfate (20 mM) 60” 98 Guanidinoethanesulfonate (20 mM) 100 Isethionic acid (20 mM) 131” TAPS (2 mM) 128” TAHS (2 mM) 219” CAPS (20 mM) 85 CAHS (20 mM) 57” AEMS (20 mM) 60a ATS (20 mM) 56” APS (20 mM) 70” TMS (20 mM) 100 M-TMS (20 mM) “Indicates significant differences of individual compounds pared to the control value (P c: 0.05).
TAPS
com-
THQS
82.U K 66.2 TAU
K -
‘4-b
45.0 K ATS
PSA
31.0 K -
Fig. 3. Schematic interrelationships of ligand binding sites for taurine (TAU) and taurine analogues (see Figs. 1 and 2) on the retinal membrane in the ATF’-dependentCa’+ uptake system. Noncompetitive inhibition by TAPS or THQS toward taurine merely indicates that their binding site(s) are other than the taurine binding site. THQS and TAPS are synergistic, which suggests that THQS (or TAPS) may induce conformational changes that enhance the inhibitory binding of TAPS (or THQS). Similarly, PSA (a partial agonist) and taurine are synergistic and, thus, PSA may induce conformational changes on the binding site of tatnine and thereby enhance the stimulatory binding of taurine. Kinetic evaluation of the data for the combined usage of taurine plus ATS (an agonist) suggests an additive effect. The V,,, for taurine is equal in value to the V_ for ATS but is greater than the V,,, for PSA. (Reprinted from Ref. 133).
21.6 K -
-0
14.4 K -
CON TAU Fig. 4. SDS-polyacrylamide gel electrophoresis and autoradiography of phosphorylated membrane proteins obtained from a P , fraction of the rat retina. Arrows designated by a and b indicate bands of protein(s) with molecular masses of = 20 kDa and = 46 kDa (Reprinted from Ref. 123).
162
A third possible function for taurine in the retina is as a regulator of signal transduction due to its effects on protein phosphorylation. It is now well established that phosphoproteins along with necessary protein kinases and/or protein phosphata~s are enriched in the nerve terminal and thus synaptic transmission may be modulated or regulated by phosphorylation processes. In this context it has been shown that taurine has an inhibitory effect on protein phosphorylation (Table III) as demonstrated by the reduced amount of incorporation of radioactive phosphate into TCA precipitates of the rat retinal preparation’12*1’3’123Y1m. In addition, taurine has no effect on retinal phosphatase activity, thus supporting the concept that it is directly affecting a kinase systemr”. It has also been demonstrated in rat retinal homogenates that taurine (20 mM) has a specific inhibitory effect on a number of proteins with molecular mass rang ing from 20 kDa to 46 kDa. However, in a retinal P, fraction, a major band of proteins with a molecular mass of approximately 20 kDa (Fig. 4) appears to be most affected”2”23~1”. Similar experiments utilizing subcellular fractions of the rat heart and rat cortex have also demonstrated that taurine has an inhibitory effect on the phosphorylation of specific proteins 1os-110~129+2*7. An inverse relationship was generally observed in the rat retina between the structnral analogues of taurine that have been shown to be stimulators of Ca2+ uptake and inhibitors of protein phosphorylation and vice versa. Analogues that were shown to be inactive in the ATPdependent Ca2+ uptake system were also inactive in the protein phosphorylation system (compare data presented in Tables I and II with data in Table III). These observations thus suggested a causal relationship between protein phospho~lation and Ca2+ uptake. However, the precise nature of this relationship and the involvement of taurine in the visual process remains to be elucidated. The implication of the involvement of taurine with both Ca2+ fluxes and phosphorylation suggests a role for taurine in signal transduction in the retina. Tbese relationships should be investigated in parallel experiments involving the purification of both systems. The isolation of specific proteins involved in both the tau~ne-in~uenced Ca2+ uptake and protein phosphorylation reactions and the potential regulatory effects of taurine on these systems should be further explored in order to define the function of taurine in the retina.
REFERENCES 1 Adler, R., Taurine uptake by chick embryo r&inaI neurons and glial cells in purified culture, 1. Neurosci. Res., 10 (1983) 369-379.
In the last few years exciting observations have been made concerning the potential functions of taurine in the retina although an underlying mechanism for the actions of taurine at the molecular level remains to be defined. This information suggests specific roles for taurine in the retina of various species inclu~ng the possibility that taurine is a conditionally essential amino acid in the human species and thus negates earlier suggestions that taurine is a dead-end metabolite of methionine metabolism. This review has presented a number of possible functions for taurine in the retina. It now remains to prove or disprove the various hypotheses that have been put forth. 11. SUMMARY
The status and potential functions of taurine in the retina have been reviewed. Taurine is present in high ~n~ntrations in the retina of all species tested, while the retinal concentrations of the enzymes necessary to synthesize taurine are presumed to vary among those species. The documented low activity of ~ysteinesulfinic acid decarboxylase, a key enzyme in taurine biosynthesis, in the livers of the cat, monkey and human possibly reflect low activity in their retinas, indicating reliance on the diet as an important source of taurine. Both highand low-amity binding proteins and uptake systems have been described for taurine in retinal tissue. Evoked release of taurine by light and other depolarizing stimuli have been well documented. Retinal pathologies including diminished ERGS and morphologic changes have been reported for animals and man deficient in taurine. Possible functions for taurine in the retina include: (1) protection of the photoreceptor - based on the shielding effects of taurine on rod outer segments exposed to light and chemicals; (2), regulation of Ca2+ transport - based on the modulatory effects of taurine on Ca2+ fluxes in the presence and absence of ATP; and (3) regulation of signal transduction - based on the inhibitory effects of taurine on protein phosphorylation.
Acktwwledgtments. The author wishes to thank Mrs. Josie L. Aleman and Mrs. Mary Alba for typing the mmuscript and Mr. Douglas Taylor for performing the photography. Preparation of the manuscript and the author’s experiments were supported by NIH Grant EYO4780.
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48
49
50 51
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59 60
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