Acknowledgements and synthesis, then it should be possible to block it I am grateful to Joel Katz, PeterMilner and Anthony Vaccarino for their valuable criticisms and suggestions. Work in the author's laboratory is supported by grant A7891 from the Natural Sciencesand EngineeringResearch Council of Canada.
by injection of a local anesthetic into appropriate discrete areas that are hypothesized to comprise the widespread neuromatrix. Data obtained in rats have shown that localized injections of lidocaine into diverse areas, such as the lateral hypothalamus 35 and the cingulum 36, produce striking decreases in experimentally produced pain. It is hoped that experiments such as these, carried out to test the neuromatrix theory, will one day lead to new approaches to the relief of phantom limb pain. If so, the theory will have served a valuable function.
Selected references 1 2 3 4
Simmel, M. (1956) Arch. Neurol. Psychiatr. 75, 69-78 Solonen, K. A. (1962) Acta Orthop. Scand. Suppl. 54, 6-37 Cohen, H. (1944) Trans. Aled. Soc. London 64, 65-99 Nathan, P. W. (1962) in The Assessment of Pain in Alan and Animals (Keele, C. A. and Smith, P., eds), pp. 129-134, Churchill-Livingstone 5 Wynn-Parry, C. B. (1980) Pain 9, 41-53 6 Melzack, R. and Bromage, P. R. (1973) Exp. Neurol. 39, 261-269 7 Bromage, P. R. and Melzack, R. (1974) Can. Anaesth. Soc. J. 21,267-274 8 Bors, E. (1951) Arch. Neurol. Psychiatr. 66, 610-631 9 Conomy, J. P. (1973) Neurology 23,842-850 10 Melzack, R. and Loeser, J. D. (1978) Pain 4, 195-210 11 Riddoch, G. (1941) Brain 64, 197-222 12 Kallio, K. E. (1950) Acta Chir. Scand. 99, 121-132
l e t ; l l : ; e l P S 11:;o t h e
edlt;OlP"
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
35 36
Katz, J. and Melzack, R. (1987) Pain 28, 51-59 Jankovic, J. and Glass, J. P. (1985) Neurology 35,432-435 Heusner,A. P. (1950) Trans. Am. Neurol. Assoc. 75, 128-131 Dorpat, T. L. (1971) Comp. Psychiatr. 12, 27-35 Kroner, K., Krebs, B., Skov, J. and Jorgensen, H. S. (1989) Pain 36, 327-334 Burke, D. C. and Woodward, J. M. (1976) in Handb. Clin. NeuroL 26, 489-499 Money, J. (1960) Arch. Gen. Psychiatr. 3,373-382 Verkuyl, A. (1969) Handb. Clin. NeuroL 4, 437-465 Mesulam, M-M. (1981) Ann. NeuroL 10, 309-325 Denny-Brown, D., Meyer, J. S. and Horenstein, S. (1952) Brain 75, 433-471 Weinstein, S. and Sersen, E. A. (1964) Cortex 1,276-290 Poeck, K. (1964) Cortex 1,269-275 Melzack, R. (1989) Can. Psychol. 30, 1-16 White, J. C. and Sweet, W. H. (1969) Pain and the Neurosurgeon C. C. Thomas Head, H. and Holmes, G. (1911-1912) Brain 34, 102-254 Changeux,J-P. and Danchin, A. (1976) Nature264, 705-712 Edelman, G. M. (1988) Neural Darwinism Basic Books Kuwada, J. Y. (1986) Science 233, 740-746 Rakic, P. (1988)in Neurobiology ofNeocortex (Rakic, P. and Singer, W., eds), pp. 5-27, Wiley Goldman-Rakic, P. S. (1988) in Neurobiology of Neocortex (Rakic, P. and Singer, W., eds), pp. 177-202, Wiley Goldman-Rakic, P. S. (1987) Child Dev. 58, 642-691 Krebs, B., Jensen,T. S., Kroner, K., Nielsen, J. and Jorgensen, H. S. (1985) in Advances in Pain Research and Therapy VoL 9 (Fields, H. L., Dubner, R. and Cervero, F., eds), pp. 425-429, Raven Tasker, R. A. R., ChoiniEre, M., Libman, S. M. and Melzack, R. (1987) Pain 31,237-248 Vaccarino, A. L. and Melzack, R. (1989) Pain 39, 213-219
......
Identification of nicotinic receptor A C h - b i n d i n g subunits
acid sequence homology and the presence of Cys 192 and Cys 193 is not sufficient for identification of functional o:-subunits. The presence of additional amino acids SIR: The review by Steinbach and that are uniquely conserved in Ifune in TINS, and the primary all o~-subunits and are known to studies referenced therein, be in close proximity to the suggest that the e~-subunits of acetylcholine-binding site should nicotinic acetylcholine receptors also be considered. Tyr 19° fulfills (nAChRs) can be identified on these criteria, since it is uniquely the basis of overall amino acid conserved in the o~-subunits and sequence homology with known has recently been shown to c~-subunits and by the presence react covalently with two very of specific amino acids such as different active-site directed afthe adjacent cysteines at pos- finity reagents. The Iophotoxin itions homologous to Cys ~92 and family of coral toxins are irreverCys ~93 of the Torpedo a-sub- sible inhibitors of both muscle and unit ~. The disulfide-linked cys- neuronal nAChRs, and these teines at positions 192 and 193 toxins have been shown to react are uniquely conserved in the o~- covalently with Tyr 19° (Refs 7, 8). subunits and they can be selec- The photoaffinity reagent tively labeled by the active-site [3H]DDF represents a different directed affinity reagent [3H]- type of active-site directed affinMBTA 2'3. In addition, reduction ity reagent that reacts primarily of these cysteines in situ or with Trp 149, Tyr 19°, Cys 192 and replacement of either cysteine Cys 193 (Ref. 9). While the funcwith serine alters receptor func- tional role of Tyr 19° is somewhat tion 4-6. Although the exact role uncertain, the charge distribution of these cysteines in receptor of [3H]DDF and the ability of function is unclear, they remain positively charged ligands to a useful diagnostic criterion for prevent reaction of the receptor identification of the o~-subunits with the coral toxins, suggest that Tyr 19° may be involved in binding of nAChRs. It is possible, however, that the quaternary ammonium group consideration of overall amino of acetylcholine 7'9. On the other
92
© 1990,ElsevierSciencePublishersLtd.(UK) 0166-2236/90/$0200
hand, the structure and reactivity of active-site directed affinity reagents such as MBTA and bromoacetylcholine suggest that Cys 192 and Cys 193 are positioned somewhere near the acyl methyl group of acetylcholine 4. Based upon the above considerations, we suggest that Tyr 19° may be a useful frame of reference for identification of the ligand-binding subunits (oc-subunits) of nAChRs.
Stewart IV. Abramson Palmer Taylor Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
References 1 Steinbach, J. H. and Ifune, C. (1989) Trends Neurosci. 12, 3-6
2 Kao, P. N. and Karlin, A. (1986) J. Biol. Chem. 261,8085-8088 3 Kao, P. N. et aL (1984)J. BioL Chem. 259, 11662-11665 4 Karlin, A. (1969) J. Gen. Physiol. 54, 245s-264s 5 Rang, H. P. and Ritter, J. M. (1971) Mol. PharmacoL 7,620-631
6 Mishina, M. et al. (1985) Nature 313, 364-369 7 Abramson, S. N., Li, Y., Culver, P. and Taylor, P. (1989) J. BioL Chem. 264, 12666-12672 8 Leutje, C. W. et aL J. Neurochem. (in press) 9 Dennis, M. et al. (1988) Biochemistry 27, 2346-2357 TINS, VOI. 13, NO. 3, 1990
by injection of a local anesthetic into appropriate discrete areas that are hypothesized to comprise the widespread neuromatrix. Data obtained in rats have shown that localized injections of lidocaine into diverse areas, such as the lateral hypothalamus 35 and the cingulum 36, produce striking decreases in experimentally produced pain. It is hoped that experiments such as these, carried out to test the neuromatrix theory, will one day lead to new approaches to the relief of phantom limb pain. If so, the theory will have served a valuable function.
Selected references 1 2 3 4
Simmel, M. (1956) Arch. Neurol. Psychiatr. 75, 69-78 Solonen, K. A. (1962) Acta Orthop. Scand. Suppl. 54, 6-37 Cohen, H. (1944) Trans. Aled. Soc. London 64, 65-99 Nathan, P. W. (1962) in The Assessment of Pain in Alan and Animals (Keele, C. A. and Smith, P., eds), pp. 129-134, Churchill-Livingstone 5 Wynn-Parry, C. B. (1980) Pain 9, 41-53 6 Melzack, R. and Bromage, P. R. (1973) Exp. Neurol. 39, 261-269 7 Bromage, P. R. and Melzack, R. (1974) Can. Anaesth. Soc. J. 21,267-274 8 Bors, E. (1951) Arch. Neurol. Psychiatr. 66, 610-631 9 Conomy, J. P. (1973) Neurology 23,842-850 10 Melzack, R. and Loeser, J. D. (1978) Pain 4, 195-210 11 Riddoch, G. (1941) Brain 64, 197-222 12 Kallio, K. E. (1950) Acta Chir. Scand. 99, 121-132
l e t ; l l : ; e l P S 11:;o t h e
edlt;OlP"
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
35 36
Katz, J. and Melzack, R. (1987) Pain 28, 51-59 Jankovic, J. and Glass, J. P. (1985) Neurology 35,432-435 Heusner,A. P. (1950) Trans. Am. Neurol. Assoc. 75, 128-131 Dorpat, T. L. (1971) Comp. Psychiatr. 12, 27-35 Kroner, K., Krebs, B., Skov, J. and Jorgensen, H. S. (1989) Pain 36, 327-334 Burke, D. C. and Woodward, J. M. (1976) in Handb. Clin. NeuroL 26, 489-499 Money, J. (1960) Arch. Gen. Psychiatr. 3,373-382 Verkuyl, A. (1969) Handb. Clin. NeuroL 4, 437-465 Mesulam, M-M. (1981) Ann. NeuroL 10, 309-325 Denny-Brown, D., Meyer, J. S. and Horenstein, S. (1952) Brain 75, 433-471 Weinstein, S. and Sersen, E. A. (1964) Cortex 1,276-290 Poeck, K. (1964) Cortex 1,269-275 Melzack, R. (1989) Can. Psychol. 30, 1-16 White, J. C. and Sweet, W. H. (1969) Pain and the Neurosurgeon C. C. Thomas Head, H. and Holmes, G. (1911-1912) Brain 34, 102-254 Changeux,J-P. and Danchin, A. (1976) Nature264, 705-712 Edelman, G. M. (1988) Neural Darwinism Basic Books Kuwada, J. Y. (1986) Science 233, 740-746 Rakic, P. (1988)in Neurobiology ofNeocortex (Rakic, P. and Singer, W., eds), pp. 5-27, Wiley Goldman-Rakic, P. S. (1988) in Neurobiology of Neocortex (Rakic, P. and Singer, W., eds), pp. 177-202, Wiley Goldman-Rakic, P. S. (1987) Child Dev. 58, 642-691 Krebs, B., Jensen,T. S., Kroner, K., Nielsen, J. and Jorgensen, H. S. (1985) in Advances in Pain Research and Therapy VoL 9 (Fields, H. L., Dubner, R. and Cervero, F., eds), pp. 425-429, Raven Tasker, R. A. R., ChoiniEre, M., Libman, S. M. and Melzack, R. (1987) Pain 31,237-248 Vaccarino, A. L. and Melzack, R. (1989) Pain 39, 213-219
......
Identification of nicotinic receptor A C h - b i n d i n g subunits
acid sequence homology and the presence of Cys 192 and Cys 193 is not sufficient for identification of functional o:-subunits. The presence of additional amino acids SIR: The review by Steinbach and that are uniquely conserved in Ifune in TINS, and the primary all o~-subunits and are known to studies referenced therein, be in close proximity to the suggest that the e~-subunits of acetylcholine-binding site should nicotinic acetylcholine receptors also be considered. Tyr 19° fulfills (nAChRs) can be identified on these criteria, since it is uniquely the basis of overall amino acid conserved in the o~-subunits and sequence homology with known has recently been shown to c~-subunits and by the presence react covalently with two very of specific amino acids such as different active-site directed afthe adjacent cysteines at pos- finity reagents. The Iophotoxin itions homologous to Cys ~92 and family of coral toxins are irreverCys ~93 of the Torpedo a-sub- sible inhibitors of both muscle and unit ~. The disulfide-linked cys- neuronal nAChRs, and these teines at positions 192 and 193 toxins have been shown to react are uniquely conserved in the o~- covalently with Tyr 19° (Refs 7, 8). subunits and they can be selec- The photoaffinity reagent tively labeled by the active-site [3H]DDF represents a different directed affinity reagent [3H]- type of active-site directed affinMBTA 2'3. In addition, reduction ity reagent that reacts primarily of these cysteines in situ or with Trp 149, Tyr 19°, Cys 192 and replacement of either cysteine Cys 193 (Ref. 9). While the funcwith serine alters receptor func- tional role of Tyr 19° is somewhat tion 4-6. Although the exact role uncertain, the charge distribution of these cysteines in receptor of [3H]DDF and the ability of function is unclear, they remain positively charged ligands to a useful diagnostic criterion for prevent reaction of the receptor identification of the o~-subunits with the coral toxins, suggest that Tyr 19° may be involved in binding of nAChRs. It is possible, however, that the quaternary ammonium group consideration of overall amino of acetylcholine 7'9. On the other
92
© 1990,ElsevierSciencePublishersLtd.(UK) 0166-2236/90/$0200
hand, the structure and reactivity of active-site directed affinity reagents such as MBTA and bromoacetylcholine suggest that Cys 192 and Cys 193 are positioned somewhere near the acyl methyl group of acetylcholine 4. Based upon the above considerations, we suggest that Tyr 19° may be a useful frame of reference for identification of the ligand-binding subunits (oc-subunits) of nAChRs.
Stewart IV. Abramson Palmer Taylor Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
References 1 Steinbach, J. H. and Ifune, C. (1989) Trends Neurosci. 12, 3-6
2 Kao, P. N. and Karlin, A. (1986) J. Biol. Chem. 261,8085-8088 3 Kao, P. N. et aL (1984)J. BioL Chem. 259, 11662-11665 4 Karlin, A. (1969) J. Gen. Physiol. 54, 245s-264s 5 Rang, H. P. and Ritter, J. M. (1971) Mol. PharmacoL 7,620-631
6 Mishina, M. et al. (1985) Nature 313, 364-369 7 Abramson, S. N., Li, Y., Culver, P. and Taylor, P. (1989) J. BioL Chem. 264, 12666-12672 8 Leutje, C. W. et aL J. Neurochem. (in press) 9 Dennis, M. et al. (1988) Biochemistry 27, 2346-2357 TINS, VOI. 13, NO. 3, 1990
