Physiology and biochemistry of vitamin D-dependent calcium binding proteins.

Physiology and biochemistry of vitamin D-dependent calcium binding

proteins

MYRON GROSS AND RAJIV KUMAR Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, 55455; and Nephrology Research Unit, Departments of Medicine, Biochemistry and Molecular Biology, Mayo Medical School, Mayo Clinic and Foundation, Rochester, Minnesota 55905

GROSS, MYRON, AND RAJIV KUMAR. Physiology and biochemistry of vitamin D-dependent calcium binding proteins. Am. J. Physiol. 259 (Renal Fluid Electrolyte Physiology 28): F195-F209, 1990.-The vitamin D-dependent calcium binding proteins (calbindins) are members of the troponinC superfamily of proteins that occur in a number of calcium-transporting tissues such as the intestine, the distal tubule of the kidney, and the placenta. They are also present in other tissues such as the brain, peripheral nervous system, pancreas, parathyroid gland, and bone. In some tissues, such as the adult brain, the proteins occur in the absence of the vitamin. The proteins bind calcium in “EF” hand structures and are “calciumsensitive” in that they undergo a conformational change on binding calcium. They appear to enhance transcellular calcium transport and are frequently present in tissues that contain the plasma membrane calcium pump.

calbindin;

calcium transport;

calcium

PURPOSE of this article is to review the physiology and biochemistry of the vitamin D-dependent calcium binding proteins. To place the importance of these proteins in perspective, we will briefly assessthe adaptations that are necessary for the maintenance of calcium balante. Calcium plays a vital role in various metabolic processes.The concentrations of calcium in extracellular fluid (ECF) and serum are maintained within a relatively narrow physiological range; deviations from this normal range are frequently associated with serious consequences. Hence, the maintenance of normal serum and ECF calcium concentrations is important. Although bone and soft tissue calcium mobilization or deposition can (and frequently do) offset decreases or increases in ECF and serum calcium concentrations, in the final analysis, the maintenance of appropriate calcium concentrations depends on the absorption and retention or the rejection of calcium by the intestine and the kidney. The parathyroid hormone-vitamin D endocrine system is the major regulator of calcium balance; changes in the concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D, either singly or together, alter the mobilization of calcium from bone and soft tissue, the efficiency of absorption of calcium from the intestine, and the reabsorption of calcium from the kidney. Several comprehensive reviews have dealt with the vitamin D-endocrine THE

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pumps; “EF” hands

system and its regulation, and readers are referred to them for details regarding the manner in which peptide and sterol hormones interact to maintain calcium balante (49, 109, 132). Increased calcium demand is met by an increase in the efficiency of calcium absorption from the intestine and an increase in the tubular reabsorption of calcium filtered in the glomeruli of the kidney. The increase in calcium retention in the intestine and the kidney is mediated by the hormonal and biologically active form of vitamin D, 125dihydroxyvitamin D (49, 109, 132). There is good evidence that protein synthesis is important in bringing about the increase in calcium transport mediated by 1,25dihydroxyvitamin D (40, 43, 67, 177). In the intestine and bone, 1,25dihydroxyvitamin D brings about its effects, at least in part, by l,%dihydroxyvitamin D-specific, receptor-dependent mechanisms that influence the expression of various genes in the nucleus (1, 7, 24, 31, 50,68,95,104,107,114,115,120,126,127, 129,135,156, 160,167,179,197-199,210,212-216,218,219,221,222). Defects in receptor structure and function that interfere with receptor-DNA interactions or hormone binding are frequently associated with calcium malabsorption and rickets (93, 94, 119, 164, 181). In the intestine 1,25dihydroxyvitamin D increases and sometimes decreases the synthesis of various proteins and alters the activity

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of various enzymes (14, 45, 78, 106, 111, 144, 174, 176, 183, 210, 212-216, 218-225). In some instances, these changes are related to changes in active calcium transport in vivo. Intestinal lipid metabolism, cyclic nucleotide levels, and the uptake of calcium by the endoplasmic reticulum and Golgi apparatus are altered by 1,25-dihydroxyvitamin D (69, 83, 123, 128, 145, 161, 162, 213). There is also evidence that 1,ZYdihydroxyvitamin D can influence calcium absorption by processes that are very rapid in onset and may not involve new protein synthesis (32, 125, 142).

The most notable of intestinal proteins whose synthesis is dependent on the presence of vitamin D are the 28kDa and 9-kDa calcium binding proteins (also referred to as calbindin-D 28k and calbindin-D&. The proteins bind calcium with high affinity (K, 2 x 106) and are widely distributed in various species and organs as detailed in Table 1. Although they are vitamin D dependent in tissues such as the intestine and kidney, there is evidence that they are not vitamin D dependent in tissues of the central nervous system. The precise manner in which the proteins increase calcium movement across epithelia remains to be defined. There is, however, compelling evidence that the diffusion of calcium is enhanced by the proteins in various model systems, that their induction parallels increases in calcium transport, and that there is a possible association between these proteins and the ATP-dependent calcium pump. Structural Characteristics of Calbindins

The primary amino acid structures of both classes of calbindins, from a variety of sources, are known (51, 52, 74, 89, 91, 95, 96, 110, 117, 150, 186, 202, 223, 226). In addition, there is information concerning the X-ray crystal structure of calbindin-Dgk (184, 185), and there is considerable information available concerning the biophysical properties of the proteins and the manner in which they bind calcium (13, 22, 34, 54, 73, 82, 91, 147). The primary structures of bovine, porcine, and murine intestinal calcium binding proteins have been obtained by amino acid sequencing techniques and have been deduced from the sequence of appropriate cDNA clones (44, 51, 52, 76, 89, 110, 118, 151; Fig. 1). The bovine protein that serves as a prototype for these proteins is a 78-amino acid protein with a molecular weight of 8,788. It is 87% and 81% homologous with the porcine and murine proteins, respectively. Hydrophilicity plots of the proteins are similar (90, 110). Each mole of the protein binds two moles of calcium (76). The high-resolution Xray crystallographic structure of a truncated form of the bovine protein has been determined (184, 185). The protein contains two helix-loop-helix structures of -29 amino acids each that bind calcium, consistent with the EF hand concept defined by Kretsinger (203). There is good agreement between the X-ray crystal structure and the predicted secondary structure of the protein (77, 99,

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1. Tissue and speciesdistribution of calbindin-D

TABLE

Species and Tissue

Cross-Reacts With Antisera Prepared to Calbindin-D From

Chicken Intestine Kidney

28 28

Uterus Hypothalamus Bone Brain Pancreas

28 ND 34 28 28

Blood Parathyroid Adrenal Esophagus Thyroid Testes

ND ND ND ND ND ND

Chicken human Chicken Chicken Chicken Chicken Chicken human Chicken Chicken Chicken Chicken Chicken Chicken

intestine, kidney intestine intestine intestine intestine intestine, kidney intestine intestine intestine intestine intestine intestine

Mouse Yolk sac Kidney

10.05 25 and 10

Intestine Placenta Uterus

9-10 ND ND

Rat intestine Human cerebellar, mouse intestine, rat intestine Rat intestine Rat intestine Rat intestine

Pig Intestine Kidney Blood -Liver . Pancreas T lyroid

9-13 12 and 25 ND 12 12 12

Pig Pig Pig Pig Pig

intestine intestine intestine intestine intestine

Human Intestine

10-28

Brain Kidney

28 28

Chicken human Chicken Chicken

intestine, kidney intestine intestine

Rat Intestine Kidney

8-13 28

Placenta Brain

10 ND

Pancreas Uterus Esophagus

ND 9-10 ND

Stomach

ND ND

Submaxillary Thymus Liver Bone

gland

ND ND ND ND ND

Skeletal

muscle

ND

Heart Lung

ND ND

Testes

ND

111) .

The amino acid sequence for chicken intestinal calbindin-D28k has been determined by Fullmer et al. (74) and Tsarbopoulos et al. (202; Fig. 2). Chicken intestinal calbindin-D2gk has been cloned and cDNA-derived amino

Approximate Molecular Mass, kDa

Chicken intestine, human kidney Rat intestine Chicken intestine, human cerebellar Human kidney Rat intestine Human cerebellar, rat intestine Human cerebellar, rat intestine Human cerebellar, rat intestine Rat intestine Rat intestine Rat intestine Rat intestine, human cerebellar Rat intestine, human cerebellar Rat intestine, human cerebellar Rat intestine Rat intestine, human cerebellar Rat intestine

cow Intestine Brain

9-11 28 9-11

Kidney

ND,

Chicken intestine Cow intestine

not determined.


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10

1

Ser

Ala

Lys

Lys

Ser

Pro

2

Ser

Ala IGln]

Lys

Ser

3

Ser

Ala

Lys

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Lys

Glu

LOU LYS Gly

Pro p]

Glu

Leu

Pro

Glu

Glu

Glu

Lys

Ser

,

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Phe

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Tyr

Ala

Ala

Lys

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lie

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Lys

Tyr Tyr

Ala Ala

Lys

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Ala Ala

Glu Glu

Lys

30

Ser

Leu

Leu

Lys

Gly

Pro

Ser

Thr

Leu

50 Asp

Glu

Leu Phe

Glu

Glu

Leu

Asp

Lys

Asn

Gly

Ser

Leu

Leu j Lys

Gly

Pro

Arg

Thr

Leu

Asp

Asp

Leu Phe

Gin

Glu

Leu

Asp

Lys

Asn

Giy

Ala

Ser

Ser

Thr

Leu

Asp

Asn

Leu Phe

Glu

Glu

Leu

Asp

Lys

Asn

.

FIG. 1. Comparison of amino acid sequences of bovine, porcine, and murine vitamin D-dependent intestinal calciumbinding proteins (CaBP). [From Kumar et al. (HO).]

70

El

Asp

Gly

Glu

Val

Ser

Phe

Glu

Glu

Phe

Gln

Val

Leu

Val

Lys

Lys

Ile

Ser

Gin

Asn

Gly

Glu

Val

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Phe

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Glu

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Val

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Val

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Lys

Ile

Ser

Gin

Asp

Gly

Glu

Val

Ser

Glu

Glu

Phe

Glu

Val

Lys

Lys

Leu

Ser

Gln

I= Bovine

CaBP

2 = Porcine

CaBP

3 = Rat CaBP

AC- TAETHLQGVEISAAQFFEIWHHYDSDGNGYMDGKELQNFIQELQQARKKAGLDLT 4 b4 Cl PEMKAR/DQYGKATDGKIGlVELAQVLPTEENFLLFFRCQQLKSSEDFMQTWRKY

DSDHSGFIDSEELKSFLKDLLQKANKQIEDSKLTEYTEIMLRMFDANNDGKLELTEL c4

WC+4

ARLLPVQENFLIKFQGVKMCAKEFNKAFEMYDQDGNGYIDENELDALLKDLCEKNK

KELDINNLATYKKSIMALSDGGKLYRAEIALILCAEEN

FIG. 2. Amino acid sequence of chicken intestinal 28 kDa calbindinD. C, indicate CNBr peptides. Peptides identified by Edman degradation analysis are circled. Other peptides were identified by mass spectrometry. [From Tsarbopoulos et al. (202).]

acid sequences have been reported by Hunziker (95) and Wilson et al. (223). The open reading frame found in cDNA clones by Wilson et al. (223) is in agreement with that found by Hunziker (95). The amino acid sequences derived from cDNA clones and determined directly are in agreement with each other. These studies taken together have provided a complete amino acid sequence for chicken intestinal calbindin-Dzsk. The protein contains 261 amino acids, six putative calcium binding sites, an acetylated NH2-terminus, and has a mol mass of 30.167 kDa. The 30.167-kDa mol mass is consistent with its amino acid composition but is larger than that determined by sodium dodecyl sulfate (SDS) gel electrophoresis (28.0 kDa). The difference in the apparent molecular mass may be due to anomalous migration on SDS gels. Analysis of the protein by mass spectrometry shows an acetylated NHZ-terminus and a possible disulfide bond (202). No other posttranslational modifications are noted. Calbindin-Dzsk binds 4 mol of calcium/mol of protein (22). Presumably, two of the putative calcium binding sites do not bind calcium or do so with a very low affinity.

Based on an analysis of the oxygen-containing residues in each putative calcium binding site, two sites may not bind calcium; however, this remains to be confirmed by additional studies. The amino acid sequences of rat, human, and bovine central nervous system calbindin-Dzsk have been determined (95, 117, 150, 186, 226). The sequence of these proteins is >79% homologous to that of chicken intestinal calbindin-DZsk. Each of the proteins contains six putative calcium binding sites (Fig. 3). Analysis of secondary structure by various algorithms sugge:Tts a similar structure for rat, human, and bovine central nervous system calbindin-D 28k and chicken intestinal calbindinD 28KThe putative calcium binding sites of the protein based on the EF hand hypothesis differ in their relative amino acid homologies. A strong amino acid homology is found between one set of three calcium binding sites and another set of three binding sites. Parmentier et al. (150) have performed an extensive analysis of interprotein and intraprotein homologies for calcium-binding proteins. A common ancestral gene may have evolved to the two, four, and six calcium-binding site proteins. Separate pathways are suggested for the evolution of each group of proteins. Slightly different evolutionary pathways have been suggested by Perret et al. (153), Hunziker (95), Desplan et al. (51), and Goodman et al. (80). A common ancestral gene and highly conserved proteins, however, are common findings of all the proposed evolutionary pathways. Sequence information from additional calcium-binding proteins may resolve the appropriate evolutionary pathways. Perret et al. (153) have determined the structure of the rat calbindin-Dgk gene. The gene is 2.5 kb long and contains three exons interrupted by two introns. The first exon contains the 5’ untranslated region; the second exon, the first EF hand; and the third exon, the second EF hand and the 3’ untranslated region. Minghetti et al. (130) have cloned and sequenced the chicken vitamin D-induced calbindin-D2sk gene. The


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Linker

Helix

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Loop

Helix

Linker

Test sequence Rat domain

I

Rat domain

II

Rat domain

III

Rat domain

IV

Rat domain

V

Rat domain

VI

FIG. 3. Amino acid sequence of rat brain calbindin-D 28~ showing EF hand binding domains. Sst 1 sites were created allowing splicing out of domains II and VI of the protein. [From Gross et al.

@U*l

..GAGCTC.. EL

gene contains 11 exons and spans 18.5 kb. The 5’ untranslated region of this gene is GC rich and contains numerous known promoter regulatory signals. The regulatory signals include a TATA box, CAT box, a glucocorticoid-responsive element, a metal-responsive element, and an enhancer-like core element. A 1,25dihydroxyvitamin D3-responsive element has been proposed from the analysis of vitamin D-regulated genes (131). The element for the chicken calbindin-DgBk gene may be AGCCCAATGGCTGAACA. The gene codes for six helix-loop-helix regions, and the exons have splice junctions that conform to the GT-AG rule. Experiments with both rat and chicken intestinal calbindin-Dzsk provide support for the “steroidlike” hormone nature of 1,25dihydroxyvitamin D,. The exact nature of 1,25-dihydroxyvitamin D3-receptor interaction with DNA sequences in the calbindin-D genes, however, remains to be elucidated. Tissue and Species Distribution of Calbindins Calbindin-D 28~and calbindin-D 9k are found in a large variety of species and tissues (Table 1). Calbindin-D28k is found in numerous chicken tissues and in many mammalian species with the highest concentrations in intestine, brain, and kidney (35, 199). Antisera produced to chicken intestinal calbindin-D28k will cross-react with calbindin-D 28kfrom most other sources. Calbindin-D28k in mammalian kidney and chicken intestine, uterus, kidney, bone, adrenal gland, and pancreas is induced by vitamin D. Calbindin-D 9k is found in many mammalian tissues including the intestine, placenta, yolk sac, uterus, kidney, liver, thyroid, blood, and pancreas (2, 4, 5, 26, 29, 46, 75, 76, 88, 110). Intestinal, yolk sac, and kidney calbindinDgk are vitamin D dependent (55, 56, 151, 152, 199). Porcine, rat, and mouse kidney each contain both calbindin-D2gk and calbindin-Dgk. Many rat tissues contain both calbindin-D 9k and calbindin-D28k (199). Antisera

Sst I (D) _ .

to intestinal calbindin-Dgk from one speciesdo not crossreact with calbindin-Dgk from tissue sources of another species, except for the reaction of anti-rat intestinal calbindin-Dgk sera with mouse calbindin-Dgk. A number of calbindin-D-like proteins have been found in mammary gland tissue (lo), bovine milk (92), rat skin (165), and parathyroid tissue (149). These proteins have molecular masses that differ from those of other calbindin-Dgk and calbindin-D2Bk proteins and do not cross-react with antisera to calbindin-Dgk or calbindin-D2sk. A few investigators have found calbindin-D28klike proteins (mol mass 20-27 kDa) in human, rat, and bovine intestinal tissue (2, 134,148,220). Multiple forms of rat kidney calbindin-D 28~ are formed by a cytosolic enzymatic factor (103). Recently calbindin has been found in the intestinalis nerve of chickens (113), chick thyroid (99), primary cultures of rat brain cells (154), dentate gyrus granule cells (l70), several areas of the rat nervous system (59), chick ultimobranchial glands (193), rat molars (57), mouse hypothalamic cell culture (155), human brain (65), and primate visual cortex (33). The wide tissue and species distribution and high degree of conservation of calbindin-D2Bk and calbindinDgk underscore an apparently vital role in cell metabolism. Although the highest concentrations of calbindinDgk and calbindin-D 28~are found in tissues that transport calcium (intestine, placenta, and kidney), significant amounts of calbindin-D28k or calbindin-Dgk are also found in many tissues that do not transport calcium (parathyroid, brain, and bone). The vitamin D dependency of calbindin-D is seen in all calcium-transporting and some, but not all, non-calcium-transporting tissues. Cellular localization of calbindins. Determination of the intra- and interintestinal cell location of the calbindins is important in understanding the physiological role of calbindin-D 28~ and calbindin-Dgk. Early investigations provided conflicting reports about the localization of


EDITORIAL

chicken intestinal calbindin-DZsk. The protein was detected in the cytoplasm and nuclei of absorptive cells (137, 140), in goblet cells (112, 116), on the surface of absorptive cells (116), in the intercellular spaces of absorptive cells, and at the apical and basal membranes (136). The localization of calbindin-D28k was found to be a function of the technique used for localization and was an apparent consequence of the solubility of calbindinDzgk in aqueous solutions. Freeze-dry and freeze-substitution techniques, which did not involve the rehydration of calbindin before fixation, localized chicken intestinal calbindin-D 28~to the cytoplasm of absorptive cells (188). The extreme water solubility of calbindin-D28k apparently led to its artifactual localization in goblet cells and on cell surfaces. Calbindin-Dgk and calbindin-Dzsk have been localized to the cytoplasm of rat duodenal (199) and organ-cultured embryonic chick duodenal absorptive cells, respectively (41). Later, the localization of calbindin-D2Bk to intestinal absorptive cells was reported in several species (4, 192). The terminal web region of rat and chick duodenal absorptive cell cytoplasm stained more intensely than other parts of the cytoplasm, suggesting higher concentrations of calbindin-Dsk and calbindin-D28k, respectively, in this region (100, 121). Euchromation of chick duodenal absorptive cell nuclei contains calbindin-D 28~ (ZOO); however, this does not appear to be a major subcellular locus (188, 191). The highest concentrations of calbindin-D28k or calbindin-Dgk are found in the duodenum relative to other segments of the intestinal tract in several species such as the chicken (194), rat (134), and cow (220). These concentrations in different parts of the intestine correlate with the presence of vitamin D-dependent active calcium transport. The distribution of calcium-transporting activity and calbindin-D2gk or calbindin-Dgk throughout the intestine is similar. The distribution of rat intestinal calbindin-D 9k messenger RNA has been determined by use of a complementary DNA probe (152). Northern blot analysis of isolated rat intestinal RNA showed a single 500- to 600-nucleotide RNA species distributed throughout the digestive tract. The highest concentration of rat intestinal calbindin-Dgk mRNA is in the duodenum with lower amounts found throughout the intestinal tract. In situ hybridization histochemistry of rat duodenal tissue, with the cDNA probe, show the mRNA localized only in the absorptive cells (198). The concentration of the mRNA is highest in the perinuclear region and lowest in the nuclear region (209). The distribution of the rat intestinal calbindin-Dgk mRNA is similar to that of the protein. The concentration of calbindin-D28k or calbindin-Dgk along the villus-crypt axis of intestinal tissue is correlated with the concentration of other possible calciumtransporting components along this axis. The highest concentrations of calbindin-D2gk or calbindin-Dgk along the duodenal villus-crypt axis are found in the villus tip in rats (194), chicks (204), and the organ-cultured embryonic chick duodenum (41). Crypt cells have been reported to be devoid of calbindin; however, after administration of 1,25-dihydroxyvitamin DS, calbindin has been detected in crypt cells. Calcium uptake and alkaline

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phosphatase activity are highest in brush-border membrane vesicles made from the villus tip of rat duodenal cells when compared with those made from other areas of the villus. A positive correlation is found between the amounts of calcium uptake, alkaline phosphatase activity, and calbindin-D along the villus-crypt axis (12). After the administration of 1,25dihydroxyvitamin D3, calcium uptake, alkaline phosphatase activity, and calbindin concentrations increase at 2 and 4 h, respectively. Similar experiments, showing a good correlation between concentrations of calbindin-D, alkaline phosphatase activity, and calcium uptake along the villus-crypt axis, have been reported by Van Corven et al. (204). 1,25-Dihydroxyvitamin D3 administration stimulates calbindin-D and alkaline phosphatase activity in rat jejunal cells; the increase, however, does not occur in parallel (180). The distribution of calbindin-D 28Kin intestinal tissues is similar to that of the plasma membrane calcium pump, suggesting that the protein and Ca2+-pump both play an important role in Ca2+ transport (17). Thus the patterns of distribution of calbindin-D along the villus-crypt axis and throughout the intestine are consistent with calbindin-D having a role in calcium transport. The distribution of calbindins in the kidney also provides insights into their possible function in calcium transport. Several workers have shown that the calbindins are localized in the distal tubule of the kidney (19, 20). This correlates with the role of the distal tubule as the site of hormone-regulated calcium absorption in this organ. Interestingly, as noted in the intestine, epitopes of the plasma membrane calcium pump are also present in the basolateral membrane of distal tubule cells (1921). This suggests that calbindins and the plasma membrane calcium pump are part of a common calciumtransporting mechanism. Calbindin-Dgk is present in the placenta and yolk sac of various species, suggesting that it may have a role in the movement of calcium from the mother to the fetus. The plasma membrane calcium pump is also localized in the membrane facing the fetus of the placental syncytiotrophoblast, once again suggesting that calbindins and the calcium pump are part of a calcium-transporting system (18). Calbindin-D 2gK and Calbindin-DgK, and Physiological Factors

Calcium Transport

Correlations between the induction and concentrations of calbindin-D28K or calbindin-Dgk in intestinal tissue and the rate and time course of calcium transport provide strong support for a role of calbindin-D28k and calbindin-D 9k in vitamin D-dependent calcium transport. Calbindin-D 28k is induced before or at the same time as calcium transport in most cases (15, 166, 210, 212216,218-225). The induction of calbindin-D28k synthesis and an increase in calcium transport is found to occur as early as 1 h after the administration of 1,X-dihydroxyvitamin DB (16). This is followed by a parallel increase in calbindin-D 28k and calcium transport and subsequently a gradual decline in both calcium transport and calbindin-D 28~ or calbindin-Dgk. Using histochemical


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techniques, Taylor (189) found an increase in calbindinDZ8k 2.5 h after the administration of l,Z&dihydroxyvitamin D,; Wasserman et al. (214) found calbindin-D28k appearance to precede an increase in calcium transport by 2 h. Six hours were required by Shinki et al. (175) to see significant increases in calcium transport and small amounts of calbindin-DZgk. In cultured embryonic duodena, calbindin-D 28~induction could be seen after 1 h and preceded an increase in calcium transport by at least 2 h (42). A few exceptions have been reported wherein induction of calcium transport appeared to precede that of calbindin-D28k (11, 182). Numerous physiological factors will alter intestinal calcium and phosphate absorption. The concentration of calbindin-D 28~and calbindin-Dgk has been measured and correlated with calcium absorption in a number of these physiological states. Glucocorticoid administration will decrease calcium absorption and intestinal calbindinD28k concentrations in chicks (63, 64, 177, 178). Calcium absorption and calbindin-D 9K concentrations are lower in the diabetic rat compared with the normal rat (169). The concentration of intestinal calbindin-D28k in laying hens is approximately three times that found in immature chicks (8). The efficiency of intestinal calcium absorption increases in chicks with the adaptation to a lowcalcium or low-phosphate diet (139). This is accompanied by an increase in intestinal calbindin-D28k. Similar results for calbindin-Dgk have been found for the rat and pig (66, 197). An inverse relationship between intestinal calcium absorption, growth rate, and age is found in rats and chickens (3, 222). That is, a decreased ability to absorb calcium is paralleled by a decrease in calbindinD28kconcentrations. In each casewherein a physiological factor alters calbindin-D concentrations, a high positive correlation is seen between calcium absorption and the amount of calbindin-D in intestinal tissue. The amount of calbindin-D 28~ in intestine is dependent on the amount of l,Z&dihydroxyvitamin D synthesized and is independent of the amount of Ca absorbed (9). Regulation of calbindin-Dz8K and calbindin-DgK. The administration of vitamin D or its active metabolites induces calbindin-D in the intestine of several species including chickens, rats, and mice. The cloning of rat intestinal calbindin-Dgk has allowed the direct quantitation of calbindin-D 9k mRNA (52). Complementary DNA (cDNA) to rat intestinal calbindin-Dgk hybridizes to a 500- to 600-nucleotide long mRNA, does not crosshybridize to mRNA for intestinal calbindin-D28k, and hybridizes to a single band in Northern analysis (51). The amount of rat intestinal calbindin-Dgk mRNA is highly correlated with the amount of calbindin-Dgk and calcium absorption throughout the rat intestine. Calbindin-Dgk mRNA is induced within 1 h following the administration of 1,25-dihydroxyvitamin D, (151, 152). In vitro induction of chicken intestinal calbindin-D28k and Ca2+ transport in an organ culture preparation of embryonic chick intestine is inhibited by inhibitors of RNA synthesis, actinomycin D, or cu-amanitin (40, 42). Emtage et al. (58) isolated polysomes from chicken intestinal tissue capable of synthesizing calbindin-D28k and demonstrated vitamin D dependence of calbindin-D28k

REVIEW

mRNA synthesis. A good correlation is found between tissue levels of calbindin-D 28kand the levels of calbindinD28k mRNA in total polysomes (37). In these experiments, polysomes were isolated from the pooled duodenal mucosa and kidneys of rachitic chickens given 13 nmol of vitamin D3 and translated in a heterologous, rabbit nuclease-treated reticulocyte system. The amount of immunoprecipitated calbindin-D28k as a percentage of the total protein synthesized by the reticulocyte system correlated well with the relative amount of calbindin-D28k found in duodenal and kidney tissue. In addition, rachitic chickens fed a low-calcium diet and given vitamin D3 had twice the amount of calbindin-D28k and apparent calbindin-D 28k mRNA as those fed a high-calcium diet. Complementary DNA probes developed for chicken intestinal calbindin-D 28k(97), have permitted direct measurements of calbindin-D 28~ mRNA levels from chicken intestine under various physiological conditions (39, 105, 201, 205, 206). Three calbindin-Dz8k mRNA species are found including a predominant species of 2,000 nucleotides and two minor species of 2,600 and 3,100 nucleotides. None of the mRNA species are found in the duodenum of rachitic chickens, and all of the species accumulate in the same time frame following the administration of 1,25-dihydroxyvitamin D3. Each of the mRNA species are found in several chicken tissues, and a close association is found between calbindin-D28k and its mRNA expression. There is evidence that vitamin D and its active metabolites may not be the exclusive regulators of calbindinD28k or calbindin-D 9k concentrations in the intestinal and kidney cells (38, 39, 178, 196). Posttra:Tscriptional events may play a role. Intestinal calbindin-Dgk shows a dose-dependent response (30) to varying doses of 1,25dihydroxyvitamin D3 in vitamin D-replete rats fed a high-calcium (1.5%) diet. The amount of intestinal calbindin-D in rats fed a low-calcium (0.06%) diet, however, is not altered by the administration of various doses of 1,25-dihydroxyvitamin D3. The intestinal calbindin-Dgk response to 1,25-dihydroxyvitamin D3 administration reaches a maximum in -1.0 and 18.0 h in vitamin Dreplete and deplete rats, respectively, on a high-calcium diet. The calbindin-D 9k response is dependent on both prior vitamin D status and calcium status. The time course of chicken intestinal calbindin-D28k synthesis by isolated polysomes with cytosolic or nuclear RNA was examined by Spencer et al. (182). Calbindin-D28k synthesis by cytosolic mRNA lags 2.5 h behind the induction of calcium absorption by 1,25-dihydroxyvitamin D, but occurs at the same time as calbindin-D28k synthesis from nuclear RNA. The synthesis of calbindin-D28k from nuclear RNA is not seen until nuclear 1,25-dihydroxyvitamin D, accumulation is at a maximum. These results suggest the presence of additional nuclear and/or cytosolic events in the regulation of calbindin-D28k. The amount of calbindin-D 28~and its mRNA have been determined in vitamin D-replete chicks fed a normal, lowcalcium, low-phosphorus, or high-calcium diet (196). Chicks were given a transcriptional inhibitor, cu-amanitin, and a translational inhibitor, cycloheximide, 2 h before a 1,25-dihydroxyvitamin D3 dose. Without inhib-


EDITORIAL

itor, the amount of calbindin-Dzsk is greater in chicks on the low-calcium and low-phosphorus diets compared with those on the high-calcium diets. The amount of calbindin-DZ8k mRNA is not affected by the dietary treatment or by cu-amanitin treatment. These results suggest posttranslational control of calbindin-D28k by calcium and/ or phosphorus. Calbindin-DzBk and its mRNA are inhibited by cycloheximide, indicating a requirement of protein synthesis for calbindin-DzBk mRNA expression. These results need to be resolved with previous work on the effects of a-amanitin (67) and correlations between calbindin-D 28~ and its mRNA (37, 105). Recent work in our laboratory has shown that 1,25dihydroxyvitamin D3-induced calcium transport is inhibited by glucocorticoids (184). Calbindin-D28k concentrati .ons are also suppressed as a result of this treatment. Glucocorticoids, however, do not alter transcriptional activity when administered with 1,25dihydroxyvitamin D3. These experiments suggest posttranscriptional controls of calbindinD28k synthesis (184). These findings suggest multi-site (perhaps transcriptional and translational) regulation of calbindin-D. Other more recent work, has also suggested posttranscriptional regulation of calbindin-D28k synthesis in kidney and intestine (38, 39). Membranes, enzymes, and calbindin-D. Calbindin-D28k may interact with enterocyte membranes and their components. Hamilton and Holdsworth (84) measured the uptake and release of calcium by mucosal cells and mitochondria isolated from the duodenum of vitamin Dreplete or -depleted chickens. The rates of calcium transport and release were higher in mucosal cells from vitamin D-treated chicks compared with those from rachitic chicks. Vitamin D treatment did not alter calcium uptake by mitochondria, a primary intracellular calcium storage site, but did increase the release of calcium from mitochondria. The incubation of cell sap, dialyzed cell sap, or purified calbindin-D 28~ from mucosal cells of vitamin Dtreated, but not rachitic, chickens with isolated mitochondria increased its rate of calcium release (85). Although this effect can be partially mimicked by ethylene glycol-bis(P-aminoethyl ether)-N,N,N’,N’-tetraacetic acid, calcium-saturated calbindin-D28k can increase the rate of calcium release from mitochondria. Thus the effect of calbindin-D 28~ on calcium release from mitochondria does not appear to be due to its ability to bind calcium. Reports have described either no effect or a stimulatory effect of calbindin-D on Ca2+-Mg2+-ATPase activity (the basolateral plasma membrane calcium pump). Morgan et al. (133), using rat kidney calbindinD28k and human erythrocyte membranes containing Ca2+-pump/Ca2+-Mg2+-ATPase, found a specific stimulatory effect of calbindin-D on Ca2+-Mg2+-ATPase activity. Ghijsen et al. (79) did not report any stimulation of Ca2+-Mg2+-ATPase ( Ca2+-pump) activity when rat intestinal calbindin-Dgk was incubated with basolateral membranes isolated from rats. Freund et al. (70), using higher concentrations of rat intestinal calbindin-Dgk than Ghijsen et al. (79) and rat duodenal mucosal cell basolateral membranes, found a two- to threefold stimulation of Ca2+-Mg2+-ATPase. In addition, they found rat intestinal calbindin-Dgk to bind to rat duodenal mucosal cell

F201

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basolateral membranes but with a lower affinity than to the brush-border membrane from the same source. Recently, Walters (208) has found an increase in Ca2+pump activity when rat duodenal basolateral membranes were exposed to calbindin. We have not found a direct effect of calbindin-D28k on Ca2+-Mg2+-ATPase activity in red blood cell ghosts (53). Differences in the source and amounts of basolateral membranes and calbindin-D used in these reports were considerable. Species, tissue, and preparation technique differences may account for the conflicting data. Alkaline phosphatase, found on the brush borders of intestinal mucosal cells, has been found to interact with calbindin-D in several systems. Leathers and Norman (ll2), using the photoaffinity probe methyl-4-azidobenzoimedate, found a Ca2+-dependent interaction between bovine alkaline phosphatase and ch .icken intestinal calbindin-D28k. Freund and Borzemsky (71) reported a twoto threefold stimulation of rat intestinal alkaline phosphatase activity with rat intestinal calbindin-Dgk and the binding of rat calbindin-Dgk to brush-border membranes. Shimura and Wasserman (173) quantitated chicken intestinal calbindin-D28k in brush-border membranes with a radioimmunoassay. Vitamin-replete, but not -depleted, chicks contained calbindin-D28k in their intestinal brush-border membranes. The calbindin-D28k could not be removed unless disrupted with detergent and protected from trypsin digestion. By use of a gel overlay technique, they found at least one protein that bound calbindin-D28k. This protein had an approximate molecular mass of 68 kDa. Calbindins

and Calcium Diffusion

It has been postulated that calbindin-D acts to buffer intracellular calcium levels (12). This hypothesis is supported by its K, for calcium of 1 X lo6 (intracellular calcium concentrations are 10-8-10-6) and its high concentration (l-3%) in intestinal tissue. On the other hand, calbindin-D concentrations are increased in animals on a low-calcium diet (7, 155) and decreased in animals on a high-calcium diet. This is inconsistent with a buffer role for calbindin-D, since its concentration would be expected to decrease and increase, respectively, under these conditions if it were merely a buffer. The protein may act as calcium shuttle to transport intestinal calcium from the brush border to the basolatera1 membrane. Feher (60) found an enhancement of calcium flux through an in vitro chamber with the addition of calbindin-D 28k and with calcium at near physiological concentrations (1 X low6 M). Kretsinger et al. (108) performed a theoretical analysis of calbindin-Dfacilitated diffusion and resolved the “too slow” free diffusion paradox described by Bronner et al. (23). Feher and Fullmer (61) found enhanced overall calcium flux in the presence of calbindin-D 9k due to an increase in the concentration of diffusible calcium. In contrast to the buffer/calcium shuttle hypothesis, Hamilton and Holdsworth (84) in in vitro experiments found an increase in calcium release from mitochondria in the presence of calbindin-D28k. The amount of calcium released was greater than that which could be bound by calbindin-


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D28k. It is notable that calbindin-Dgk is highly conserved relative to other calcium-binding proteins. This degree of conservation is unlikely and unnecessary for a protein acting only as a buffer/calcium shuttle. Calbindin-DgBk is highly conserved even in certain linker regions (96). This observation suggests additional functions for calbindin-D. Binding

of Calcium and its Analogues to Calbindin-D

The predominant functional property of calbindin-D is the binding of calcium. This property of bovine, porcine, and chicken intestinal calbindin-D has been studied with spectroscopic methods. Circular dichroism spectroscopy of divalent and trivalent cation binding to porcine of tyrointestinal calbindin-D 9k reveals a perturbation sine and phenylalanine residues without a significant change in peptide backbone absorption (57). The affinity of various cations for the protein is related to their ionic radius with calcium having a K, of -2 x 106. The majority of the absorbance change with cation binding is due to the single tyrosine residue found in porcine intestinal calbindin-D gk. This residue appears to be located in a cleft in the protein, and its exposure to solvent is not altered by the binding of calcium. The tyrosine hydroxy group has a very high pK and does not ionize significantly below pH 12. Tyrosine fluorescence can be reversibly quenched by a lysine residue with a pK of 10.05 when calcium is bound to the protein. Based on an X-ray crystallographic structure of bovine calbindin-Dgk (184)) a model is suggested for the interaction of tyrosine-16 with other amino acid residues in porcine intestinal calbindin-D gk, wherein the removal of calcium from porcine intestinal calbindin-Dgk results in an increase in the number of negative charges near tyrosine-16 and specifically brings glutamate-30 closer to tyrosine-16 (54). Terbium, an analogue of calcium (91), binds sequentially to the two cation binding sites on porcine intestinal calbindin-D 9k (146). From energy transfer experiments, bound terbium is located -20 A from the tyrosine residue. The affinity of the first site filled is significantly higher than the second site filled by terbium. Filling of the first site results in enhanced tyrosine fluorescence, whereas filling of the second site quenches tyrosine fluorescence. Based on alterations in tyrosine fluorescence on calcium binding it is likely that calbindin-Dgk undergoes a conformational change in binding to calcium. A conformational change in porcine intestinal calbindin-Dgk is found with calcium binding by circular dichroism spectroscopy and is consistent with a change in the a-helical content of the protein (34). Cadmium- 113 and calcium-43 nuclear magnetic resonance (NMR) of the cadmium- and calcium-bound porcine intestinal calbindin-Dgk shows an interaction between the two calcium sites that may be cooperative (207). ‘H-NMR experiments show changes in the tertiary structure of the protein with calcium binding. Other ‘H-NMR experiments do not support the calcium-43 NMR results and suggest the random binding of calcium to two independent sites with equivalent association constants (172). ‘H-NMR studies of ytterbium-bound porcine intestinal calbindin-Dgk have allowed the calculation of Yb3+-proton distance for nuclei

REVIEW

in the metal binding site (171). NMR studies of bovine intestinal calbindin-D 9k have suggested changes in the tertiary structure of the proteins with calcium binding (13) Chicken intestinal calbindin-D28k has a structure significantly different from that of porcine or bovine calbindin-Dgk. The protein is substantially larger with six EFhand regions. Equilibrium dialysis experiments have demonstrated the binding of calcium and lead to chicken intestinal calbindin-D 28~ (22,73). The binding of calcium and terbium to the protein have been studied by terbium fluorescence, circular dichroism, and intrinsic protein fluorescence techniques by our laboratory (82). Chicken intestinal calbindin-D28k has three high-affinity terbium binding sites as indicated by the sharp transition in terbium fluorescence at a terbium:calbindin-D28K stoichiometry of 3.0. These sites can be resolved into one very high affinity site (site A) and two other sites (sites B and C) by a comparison of terbium fluorescence measurements. One site, site A, is filled with terbium before sites B and C, indicating that site A has a higher affinity for terbium than sites B and C. Calcium can displace terbium bound to sites A, B, and C on the protein. The addition of EDTA to the calcium-saturated protein results in a 25% decrease in intrinsic protein fluorescence. The titration of EDTA-treated chicken intestinal calbindin-D2gk with calcium results in the recovery of its intrinsic protein fluorescence. A reversible calcium-dependent change in the ellipticity of the protein is seen in circular dichroism experiments. These results indicate the presence of binding sites on the protein with different affinities for calcium and terbium and a conformational change in the protein with calcium binding. Energy transfer experiments provided for the localization of site A, B, and C to sites I, III, and IV, respectively, of chicken intestinal calbindin-D 28k. To further localize and examine the calcium-binding sites of calbindin, we have made recombinant calbindin-D2Bk (81). Rat brain calbindinD28k was cloned, and the full-length protein was expressed in E. coli. Several mutated proteins were produced by removal of the DNA segments coding for sites II, VI, and II plus VI (Fig. 3). Native chicken, intestinal and rat brain calbindin-D 28~ were isolated and compared with the recombinant proteins. The recombinant proteins have the expected molecular weights as determined by SDS-polyacrylamide gel electrophoresis. The amino acid composition of full-length and native rat brain calbindin-D2gK are essentially identical. All of the recombinant proteins bind radioactive calcium. Moreover, the specific radioactive calcium-binding activity of the proteins does not appear to be altered by the removal of sites II and VI. Sites II and VI, therefore, may not be essential for the binding of calcium. These proteins are being used to further examine the calcium-binding sites of calbindin-D28k. Conclusions Physiological role of calbindins. The wide species and tissue distribution of calbindin-D and its evolutionary conservation suggest an important and fundamental role of the protein in the metabolism of numerous cell types.


EDITORIAL

The highest concentrations of calbindin-Dgk and calbindin-DZ8k are found in calcium-transporting tissues such as intestine, kidney, and placenta. Smaller, but significant amounts of calbindin-DZ8k and calbindin-Dgk are found in nonepithelial tissues that do not transport calcium, such as bone, parathyroid, and brain. These findings support the concept that calbindin-D has a role in calcium transport but also suggest that calbindin-D is multifunctional and has tissue-dependent roles, or that calbindin-D has a role common to calcium-transporting and non-calcium transporting tissues, which is accentuated in calcium-transporting tissues. Extensive evidence supports a role for calbindin-D in calcium transport. The pattern of calbindin-D distribution in the intestine and along its villus-crypt axis correlates well with known sites of calcium uptake and absorption. Correlations between the time course of calcium absorption and calbindin-DZ8k or calbindin-Dgk induction as well as the concentrations of calbindin-D28k or calbindinDgk in intestinal tissue and the rate of calcium transport are consistent with a role for calbindin-Dgk and calbindin-Dzsk in vitamin D-dependent calcium transport. The role of calbindins in enhancing calcium diffusion has been alluded to above. It has been proposed that calbindin-Dzgk is a calcium transport molecule; localization of calbindin-D 28~ to predominantly the cytosolic component of intestinal cells would appear to preclude this possibility. Calbindin, however, may interact with calcium transport or other molecules and act as a calciumsensitive regulator protein. Calbindin-D has the general features characteristic of known calcium-sensitive regulator proteins such as troponin C and calmodulin, including a conformational change in the protein with calcium binding and the binding of calcium to EF-hand regions of the protein. A calcium-dependent interaction of calbindin-D 28~ with alkaline phosphatase has been shown and the localization of calbindin-D along the villus-crypt axis in the intestine parallels that of alkaline phosphatase. Calbindin-D has been reported to alter Ca2+-Mg2+-ATPase/Ca2+-pump activity; calbindin colocalizes with the plasma membrane Ca2+ pump in several tissues. Calbindin-D 28~ also binds to brush-border membrane protein(s). Thus the protein may potentially interact with many proteins, transporting enzymes, or pumps to help regulate calcium concentrations in the cell. Finally, another possibility, based on sequential localization studies, is that calbindins play a role in cell differentiation. Calbindin appears to be expressed at only certain times during thyroid and testicular development (99, 101). Similar situations may exist in other tissues. The investigation of the role of calbindin-D in cell function will undoubtedly continue to be an intense area of investigation in the coming years. This study was supported by National Institute of Diabetes Digestive and Kidney Diseases Grant DK-25409 to R. Kumar. Address for reprint requests: R. Kumar, Nephrology Research Mayo Clinic and Foundation, Rochester, MN 55905.

REVIEW

2.

3.

4.

5.

6.

7.

8.

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10. 11.

12.

13.

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17.

and 18. Unit,

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Physiology of Calcium, Phosphate, Magnesium and Vitamin D.

Calcium-binding proteins.

Comparative biochemistry and physiology of gut hormones.

Biochemistry and physiology of oviductal secretions.

Prospects for comparative physiology and biochemistry.

Intestinal and placental calcium-binding proteins in vitamin D-deprived or -supplemented rats.

Demonstration of two different vitamin D-dependent calcium-binding proteins in rat intestinal mucosa.

Calcium binding proteins and calcium signaling in prokaryotes.

Biochemistry and physiology of pyrroloquinoline quinone and quinoprotein dehydrogenases.

Vitamin B12 binding proteins in bovine serum.

Physiology and biochemistry of the stigmatic fluid of Petunia hybrida.

Serum vitamin B12- binding proteins in neutropenia.

Biochemistry and physiology of a family of eel natriuretic peptides.

Some unresolved issues in the physiology and biochemistry of phototransduction.

Calcium-binding proteins in the vorticellid spasmoneme.

Calcium binding by spinach stromal proteins.

Phospholipid-binding proteins in calcium-dependent exocytosis.

Calcium-binding proteins in the nervous system.

The physiology of vitamin D-far more than calcium and bone.

Biochemistry of fish antifreeze proteins.

Case studies: games: three examples from biochemistry, physiology and pharmacology.

Immunoperoxidase localization of vitamin D dependent calcium binding protein.

Effects of the sex steroid hormones and vitamin D3 on calcium-binding proteins in the chick shell gland.

Fruit Calcium: Transport and Physiology.