Physiological Reviews, Vol 59, 165-227, Copyright © 1979 by American Physiological Society

JOURNAL ARTICLE

Control of acetylcholine receptors in skeletal muscle

D. M. Fambrough

An ACh receptor is the molecular entity that, in its native habitat, possesses the binding sites for ACh and all the other components required to generate the ion channels mediating the ACh response. Narrower definitions of an ACh receptor (as the binding site for ACh or the polypeptide chain that is folded to form the binding site) could lead to semantic arguments about receptor structure. Experimentally, ACh receptors are defined by their total function (when electrophysiological tests are used) or by ligand binding. There is no evidence that the ligand-binding portions of ACh receptors ever exist in vivo without the associated channel-forming mechanism and vice versa. Most data are consistent with the idea that detergent-solubilized glycoproteins retaining the ACh binding sites of the receptor also include the channel-forming components, although it appears that the mechanism is prone to denaturation or proteolytic damage. Studies of receptor-rich membranes and of solubilized receptor glycoprotein have not yet yielded a totally satisfactory image of receptor structure. Most evidence favors an ACh receptor composed of three or four different types of glycosylated polypeptide chains organized into a unit of aggregate molecular weight about 300,000--400,000 daltons. Plasma membranes are dynamic structures in two different ways. First, their constituent molecules are in rapid thermal motion and, when these molecules are not tethered to extramembranous structures or mired in large aggregates, they fairly rapidly change their position in the plane of the lipid bilayer. Second, all membrane components are continually being synthesized and degraded. Acetylcholine receptors participate in both aspects of this dynamism. In this review it is proposed that the number and the distribution of ACh receptors in skeletal muscle are controlled by modulation of receptor metabolism and modulation of associations between receptor molecules or between receptors and other, as yet unidentified, elements in neuromuscular junctions and at extrajunctional sites where receptors are clustered. The arrangements of receptors in skeletal muscle and the total number of receptors in skeletal muscle may be regulated by separate mechanisms. Clusters of ACh receptors apparently can form spontaneously in extrajunctional areas of denervated muscles and in tissue-cultured embryonic muscle. Such clusters may be positionally stable and the receptor molecules in them may be highly restricted in mobility. Nevertheless, these receptors have average lifetimes on the order of 20 h, just like the nonclustered, mobile extrajunctional receptors. Receptor clusters also form at sites of innervation. In the chick embryo the junctional receptor molecules remain short-lived. The metabolism of ACh receptors is highly regulated. The biosynthesis of receptors commences during myogenesis at about the time myogenic cells become competent to fuse. Later, biosynthesis is dramatically repressed by muscle activity and possibly by other factors...

This article has been cited by other articles:

				S. Tabata, Y. Takemura, M. Kobayashi, M. Ikeda, S. Nishimura, Y. Sato, R. Tatsumi, Y. Ikeuchi, and H. Iwamoto Mechanism of Ca2+ increase in myoblasts derived from chicken embryos J. Electron Microsc. (Tokyo), October 1, 2006; 55(5): 265 - 271. [Abstract] [Full Text] [PDF]

				C. M. McCann, J. Bracamontes, J. H. Steinbach, and J. R. Sanes The cholinergic antagonist {alpha}-bungarotoxin also binds and blocks a subset of GABA receptors PNAS, March 28, 2006; 103(13): 5149 - 5154. [Abstract] [Full Text] [PDF]

				E. Bruneau, D. Sutter, R. I. Hume, and M. Akaaboune Identification of Nicotinic Acetylcholine Receptor Recycling and Its Role in Maintaining Receptor Density at the Neuromuscular Junction In Vivo J. Neurosci., October 26, 2005; 25(43): 9949 - 9959. [Abstract] [Full Text] [PDF]

				K. S. Kim, J. W. Jeon, M. S. Koh, J. H. Shim, S. Y. Cho, and J. K. Suh The Duration of Immobilization Causes the Changing Pharmacodynamics of Mivacurium and Rocuronium in Rabbits Anesth. Analg., February 1, 2003; 96(2): 438 - 442. [Abstract] [Full Text] [PDF]

				M. Thoby-Brisson and J. Simmers Long-Term Neuromodulatory Regulation of a Motor Pattern-Generating Network: Maintenance of Synaptic Efficacy and Oscillatory Properties J Neurophysiol, December 1, 2002; 88(6): 2942 - 2953. [Abstract] [Full Text] [PDF]

				A. Mizrahi, P. S. Dickinson, P. Kloppenburg, V. Fenelon, D. J. Baro, R. M. Harris-Warrick, P. Meyrand, and J. Simmers Long-Term Maintenance of Channel Distribution in a Central Pattern Generator Neuron by Neuromodulatory Inputs Revealed by Decentralization in Organ Culture J. Neurosci., September 15, 2001; 21(18): 7331 - 7339. [Abstract] [Full Text] [PDF]

				Z.-Z. Wang, A. Mathias, M. Gautam, and Z. W. Hall Metabolic Stabilization of Muscle Nicotinic Acetylcholine Receptor by Rapsyn J. Neurosci., March 15, 1999; 19(6): 1998 - 2007. [Abstract] [Full Text] [PDF]

				K. S. Kim, J. C. Shim, J. H. Jun, K. H. Lee, and C. W. Chung Rabbits Treated with Chronic Isepamicin Are Resistant to Mivacurium and Rocuronium Anesth. Analg., March 1, 1999; 88(3): 654 - 654. [Abstract] [Full Text] [PDF]

				M. Thoby-Brisson and J. Simmers Neuromodulatory Inputs Maintain Expression of a Lobster Motor Pattern-Generating Network in a Modulation-Dependent State: Evidence from Long-Term Decentralization In Vitro J. Neurosci., March 15, 1998; 18(6): 2212 - 2225. [Abstract] [Full Text] [PDF]

				R. Xu and M. M. Salpeter Acetylcholine Receptors in Innervated Muscles of Dystrophic mdx Mice Degrade as after Denervation J. Neurosci., November 1, 1997; 17(21): 8194 - 8200. [Abstract] [Full Text] [PDF]

				P. Martin, A. Ettinger, and Sanes JR A synaptic localization domain in the synaptic cleft protein laminin beta 2 (s-laminin) Science, July 21, 1995; 269(5222): 413 - 416. [Abstract] [PDF]

				D. B. Drachman Myasthenia Gravis N. Engl. J. Med., June 23, 1994; 330(25): 1797 - 1810. [Full Text]

				S. Jo and S. Burden Synaptic basal lamina contains a signal for synapse-specific transcription Development, January 7, 1992; 115(3): 673 - 680. [Abstract] [PDF]

				T Claudio, W. Green, D. Hartman, D Hayden, H. Paulson, F. Sigworth, S. Sine, and A Swedlund Genetic reconstitution of functional acetylcholine receptor channels in mouse fibroblasts Science, December 18, 1987; 238(4834): 1688 - 1694. [Abstract] [PDF]

				S. Waxman and J. Ritchie Organization of ion channels in the myelinated nerve fiber Science, June 28, 1985; 228(4707): 1502 - 1507. [Abstract] [PDF]

				J. Changeux, A Devillers-Thiery, and P Chemouilli Acetylcholine receptor: an allosteric protein Science, September 21, 1984; 225(4668): 1335 - 1345. [Abstract] [PDF]

				C. Andrew, D. Drachman, A Pestronk, and O Narayan Susceptibility of skeletal muscle to Coxsackie A2 virus infection: effects of botulinum toxin and denervation Science, February 17, 1984; 223(4637): 714 - 716. [Abstract] [PDF]

				E. Stanley and D. Drachman Rapid degradation of "new" acetylcholine receptors at neuromuscular junctions Science, October 7, 1983; 222(4619): 67 - 69. [Abstract] [PDF]

				J.-P. Changeux, F. Bon, J. Cartaud, A. Devillers-Thiery, J. Giraudat, T. Heidmann, B. Holton, H.-O. Nghiem, J.-L. Popot, R. Van Rapenbusch, et al. Allosteric Properties of the Acetylcholine Receptor Protein from Torpedo marmorata Cold Spring Harb Symp Quant Biol, January 1, 1983; 48(0): 35 - 52. [Abstract] [PDF]

				Z.W. Hall, M.-P. Roisin, Y. Gu, and P.D. Gorin A Developmental Change in the Immunological Properties of Acetylcholine Receptors at the Rat Neuromuscular Junction Cold Spring Harb Symp Quant Biol, January 1, 1983; 48(0): 101 - 108. [Abstract] [PDF]

				T. Lentz, T. Burrage, A. Smith, J Crick, and G. Tignor Is the acetylcholine receptor a rabies virus receptor? Science, January 8, 1982; 215(4529): 182 - 184. [Abstract] [PDF]

				T. Levitt, R. Loring, and M. Salpeter Neuronal control of acetylcholine receptor turnover rate at a vertebrate neuromuscular junction Science, October 31, 1980; 210(4469): 550 - 551. [Abstract] [PDF]

				A Pestronk and D. Drachman Lithium reduces the number of acetylcholine receptors in skeletal muscle Science, October 17, 1980; 210(4467): 342 - 343. [Abstract] [PDF]

				R. Holland and M. Brown Postsynaptic transmission block can cause terminal sprouting of a motor nerve Science, February 8, 1980; 207(4431): 649 - 651. [Abstract] [PDF]