On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents

  • D. Colquhoun
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 79)

Abstract

In this chapter, the evidence concerning the mechanism of postsynaptic action of neuromuscular blocking agents will be discussed. Although it could certainly be argued that the important facts about tubocurarine were all known long before the voltage clamp was invented, it could not be argued that the reasons for its behaviour were understood. The emphasis in this chapter will be on the fundamental molecular effects of the drugs, rather than on the phenomena which they are empirically observed to produce. These limitations on the scope of this chapter reduce considerably the work that will be dealt with in any detail, because the amount of knowledge about molecular mechanisms of action is surprisingly small. This statement may seem odd in view of the vast amount of work that has been done on the neuromuscular junction, and on drugs that affect it. But inspection of the literature soon reveals that almost all of this work is done by methods that are not capable of giving rigorous information about mechanisms. For example, a blocking drug is often described as “competitive” for no better reason than that it fails to produce a depolarization; indeed, even membrane potential often is not directly observed, so perhaps one should say that it fails to behave as though it were producing a depolarization. This sort of statement can surely not be defended by any pharmacologist as an adequate definition of what is meant by “competitive”. Similarly, the details of the mechanisms of action of those blockers that produce a depolarization have, with a few exceptions, yet to be investigated by modern electrophysiological methods.

Keywords

Nicotine Choline Sine Acetyl Halothane 

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References

  1. Adams DJ, Colquhoun D (1984) Current relaxations with high agonist concentrations. Do acetylcholine and suberyldicholine block ion channels in frog muscle? J Physiol (Lond) 341:22–23PGoogle Scholar
  2. Adams DJ, Dwyer TM, Hille B (1980) The permeability of endplate channels to monovalent and divalent metal cations. J Gen Physiol 75:493–510PubMedGoogle Scholar
  3. Adams PR (1975 a) Kinetics of agonist conductance changes during hyperpolarization at frog endplates. Br J Pharmacol 53:308PubMedGoogle Scholar
  4. Adams PR (1975b) A study of desensitization using voltage clamp. Pflugers Arch 360:135–144PubMedGoogle Scholar
  5. Adams PR (1976) Drug blockade of open end-plate channels. J Physiol (Lond) 260:531–552Google Scholar
  6. Adams PR (1977) Voltage jump analysis of procaine action at the frog end-plate. J Physiol (Lond) 268:291–318Google Scholar
  7. Adams PR (1980) Aspects of synaptic potential generation. In: Pinsker HM (ed) Information processing in the nervous system. Raven New YorkGoogle Scholar
  8. Adams PR (1981) Acetylcholine receptor kinetics. J Membr Biol 58:161–174PubMedGoogle Scholar
  9. Adams PR, Sakmann B (1978) Decamethonium both opens and blocks endplate channels. Proc Natl Acad Sci USA 75:2994–2998PubMedGoogle Scholar
  10. Adrian RH, Marshall MW (1977) Sodium current in mammalian muscle. J Physiol (Lond) 268:223–250Google Scholar
  11. Albuquerque EX, Adler M, Spivak CE, Aguayo L (1980) Mechanism of nicotinic channel activation and blockade. Ann N Y Acad Sci 358:204–238PubMedGoogle Scholar
  12. Anderson CR, Stevens CF (1973) Voltage clamp analysis of acetylcholine produced endplate current fluctuations at frog neuromuscular junction. J Physiol (Lond) 235:655–691Google Scholar
  13. Armstrong CM (1971) Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58:413–437PubMedGoogle Scholar
  14. Armstrong DL, Lester HA (1979) The kinetics of tubocurarine action and restricted diffusion within the synaptic cleft. J Physiol (Lond) 294:365–386Google Scholar
  15. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58Google Scholar
  16. Ascher P, Large WA, Rang HP (1979) Studies on the mechanism of action of acetylcholine antagonists on rat parasympathetic ganglion cells. J Physiol (Lond) 295:139–170Google Scholar
  17. Barnard EA, Coates V, Dolly JO, Mallick B (1977) Binding of a-bungarotoxin and cholinergic ligands to acetylcholine receptors in the membrane of skeletal muscle. Cell Biol Int Rep 1:99–106PubMedGoogle Scholar
  18. Blackman JG (1959) The pharmacology of depressor bases. PhD Thesis, University of New ZealandGoogle Scholar
  19. Blackman JG (1970) Dependence on membrane potential of the blocking action of hexa-methonium at a sympathetic ganglionic synapse. Proc University of Otago Med Sch 48:4–5Google Scholar
  20. Blackman JG, Gauldie RW, Milne RJ (1975) Interaction of competitive antagonists: the anti-curare action of hexamethonium and other skeletal neuromuscular junction. Br J Pharmacol 54:91–100PubMedGoogle Scholar
  21. Boheim G, Hanke W, Barrantes FJ, Eibl H, Sakmann B, Fels G, Maelicke A (1981) Agonist-activated ionic channels in acetylcholine receptor reconstituted into plainer lipid bilayers. Proc Natl Acad Sci USA 78:3586–3590PubMedGoogle Scholar
  22. Bonner R, Barrantes FJ, Jovin TM (1976) Kinetics of agonist-induced intrinsic fluorescence changes in membrane-bound acetylcholine receptor. Nature 263:429–431PubMedGoogle Scholar
  23. Bowman WC (1980) Pharmacology of neuromuscular function. Wright, BristolGoogle Scholar
  24. Boyd ND, Cohen JB (1980 a) Kinetics of binding of [3H]acetylcholine and [3H]carbamyl-choline to Torpedo postsynaptic membranes: slow conformational transition of the cholinergic receptor. Biochemistry 19:5344–5353PubMedGoogle Scholar
  25. Boyd ND, Cohen JB (1980 b) Kinetics of binding of [3H]acetylcholine to Torpedo postsynaptic membranes: association and dissociation rate constants by rapid mixing and ultrafiltration. Biochemistry 19:5353–5358PubMedGoogle Scholar
  26. Bryant SH, Morales-Aguilera A (1971) Chloride conductance in normal and myotonic muscle fibres and the action of monocarboxylic aromatic acids. J Physiol (Lond) 219:367–383Google Scholar
  27. Burns BD, Paton WDM (1951) Depolarization of the motor end-plate by decamethonium and acetylcholine. J Physiol (Lond) 115:41–73Google Scholar
  28. Case R, Creese R, Dixon WJ, Massey FJ, Taylor DB (1977) Movement of labelled decamethonium in muscle fibres of the rat. J Physiol (Lond) 272:283–294Google Scholar
  29. Cash DJ, Aoshima H, Hess GP (1981) Acetylcholine-induced cation across cell membranes and inactivation of the acetylcholine receptor: chemical kinetic measurements in the millisecond time region. Proc Natl Acad Sci USA 78:3318–3322PubMedGoogle Scholar
  30. Castillo J del, Katz B (1957 a) Interaction at end-plate receptors between different choline derivatives. Proc R Soc Lond B Biol Sci 146:369–381Google Scholar
  31. Castillo J del, Katz B (1957 b) A study of curare action with an electrical micro-method. Proc R Soc Lond B Biol Sci 146:339–356Google Scholar
  32. Claudio T, Ballivet M, Patrick J, Heinemann S (1983) Nucleotide and deduced aminoacid sequences of Torpedo californica acetylcholine receptor y subunit. Proc Natl Acad Sci USA 80:1111–1115PubMedGoogle Scholar
  33. Cohen JB, Weber M, Changeux J-P (1974) Effects of local anesthetics and calcium on the interaction of cholinergic ligands with the nicotinic receptor protein from Torpedo marmorata. Mol Pharmacol 10:904–932Google Scholar
  34. Colquhoun D (1973) The relation between classical and cooperative models for drug action. In: Rang HP (ed) Drug receptors. Macmillan, London, pp 149–182Google Scholar
  35. Colquhoun D (1975) Mechanisms of drug action at the voluntary muscle end-plate. Annu Rev Pharmacol 15:307–325PubMedGoogle Scholar
  36. Colquhoun D (1978) Noise: a tool for drug receptor investigation. In: Bolis L, Straub RW (eds) Cell membrane receptors for drugs and hormones. Raven, New YorkGoogle Scholar
  37. Colquhoun D (1979) The link between drug binding and response: theories and observations. In: O’Brien RD (ed) The receptors: a comprehensive treatise. Plenum, New YorkGoogle Scholar
  38. Colquhoun D (1980) Competitive block and ion channel block as mechanisms of antagonist action on the skeletal muscle end-plate. Adv Biochem Psychopharmacol 21:67–80PubMedGoogle Scholar
  39. Colquhoun D (1981a) How fast do drugs work? Trends Pharmacol Sci 2:212–217Google Scholar
  40. (Reprinted in Lamble J (ed) Towards understanding receptors. Elsevier, Amsterdam, 1981)Google Scholar
  41. Colquhoun D (1981b) The kinetics of conductance changes at nicotinic receptors of the muscle end-plate and of ganglia. In: Birdsall N (ed) Drug receptors and their effectors. Macmillan, LondonGoogle Scholar
  42. Colquhoun D, Hawkes AG (1977) Relaxation and fluctuations of membrane currents that flow through drug-operated ion channels. Proc R Soc Lond [Biol] B199:231–262Google Scholar
  43. Colquhoun D, Hawkes AG (1981) On the stochastic properties of single ion channels. Proc Roy Soc Lond [Biol] B211:205–235Google Scholar
  44. Colquhoun D, Hawkes AG (1982) On the stochastic properties of bursts of single ion channel openings and of clusters of bursts. Philos Trans R Soc Lond [Biol] B300:l-59Google Scholar
  45. Colquhoun D, Hawkes AG (1983) The principles of the stochastic interpretation of ion channel mechanisms. In: Sakmann B, Neher E (eds) Single channel recording. Plenum, New YorkGoogle Scholar
  46. Colquhoun D, Rang HP (1976) Effects of inhibitors on the binding of iodinated a-bungaro-toxin to acetylcholine receptors in rat muscle. Mol pharmacol 12:519–535PubMedGoogle Scholar
  47. Colquhoun D, Sakmann B (1981) Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels. Nature 294:464–466PubMedGoogle Scholar
  48. Colquhoun D, Sakmann B (1983) Bursts of openings in transmitter-activated ion channels. In: Sakmann B, Neher E (eds) Single channel recording. Plenum, New YorkGoogle Scholar
  49. Colquhoun D, Sheridan RE (1981) The modes of action of gallamine. Proc R Soc Lond [Biol] B211:181–203Google Scholar
  50. Colquhoun D, Sheridan RE (1982) The effect of tubocurarine competition on the kinetics of agonist action on the nicotine receptor. Br J Pharmacol 75:77–86PubMedGoogle Scholar
  51. Colquhoun D, Dionne VE, Steinbach JH, Stevens CF (1975) Conductance of channels openend by acetylcholine-like drugs in muscle end-plate. Nature 253:204–206PubMedGoogle Scholar
  52. Colquhoun D, Large WA, Rang HP (1977) An analysis of the action of a false transmitter at the neuromuscular junction. J Physiol (Lond) 266:361–395Google Scholar
  53. Colquhoun D, Dreyer F, Sheridan RE (1979) The actions of tubocurarine at the frog neuromuscular junction. J Physiol (Lond) 293:247–284Google Scholar
  54. Conti-Tronconi BM, Gotti CM, Hunkapiller MW, Raftery MA (1982) Mammalian muscle acetylcholine receptor: a supramolecular structure formed by four related proteins. Science 218:1227–1229PubMedGoogle Scholar
  55. Creese R, Franklin GI, Mitchell LD (1976) Two mechanisms for spontaneous recovery from depolarising drugs in rat muscle. Nature 261:416–417PubMedGoogle Scholar
  56. Creese R, Franklin GI, Mitchell LD (1977) Sodium entry in rat diaphragm induced by depolarizing drugs. J Physiol (Lond) 272:295–316Google Scholar
  57. Creese R, Humphrey PPA, Mitchell LD (1983) Recovery from decamethonium rat muscle and denervated guinea pig diaphragm. J Physiol (Lond) 334:365–377Google Scholar
  58. Cull-Candy SG (1981) Synaptic noise and transmitter action at nerve muscle junctions. Trends Neurosci 4:1–3Google Scholar
  59. Cull-Candy SG, Miledi R, Trautmann A (1979) End-plate currents and acetylcholine noise at normal and myasthenic human end-plates. J Physiol (Lond) 287:247–265Google Scholar
  60. Dionne VE, Steinbach JH, Stevens CF (1978) An analysis of the dose-response relationship at voltage-clamped frog neuromuscular junctions. J Physiol (Lond) 281:421–444Google Scholar
  61. Dreyer F, Muller K-D, Peper K, Sterz R (1976) The M omohyoideus of the mouse as a convenient mammalian muscle preparation. Pflugers Arch 367:115–122PubMedGoogle Scholar
  62. Dreyer F, Peper K, Sterz R (1978) Determination of dose-responses curves by quantitative ionophoresis at the frog neuromuscular junction. J Physiol (Lond) 281:395–419Google Scholar
  63. Dunn SMJ, Blanchard SG, Raftery MA (1980) Kinetics of carbamylcholine binding to membrane-bound acetylcholine receptor monitored by fluorescence changes of a covalently bound probe. Biochemistry 19:5645–5652PubMedGoogle Scholar
  64. Duval A, Leoty C (1978) Ionic currents in mammalian fast skeletal muscle. J Physiol (Lond) 278:403–423Google Scholar
  65. Feltz A, Trautmann A (1982) Desensitization at the frog neuromuscular junction: a biphasic process. J Physiol (Lond) 322:257–272Google Scholar
  66. Feltz A, Large WA, Trautmann A (1977) Analysis of atropine action at the frog neuromuscular junction. J Physiol (Lond) 269:109–130Google Scholar
  67. Ferry CB, Marshall AR (1973) Anti-curare effect of hexamethonium at the mammalian neuromuscular junction. Br J Pharmacol 47:353–362PubMedGoogle Scholar
  68. Fletcher P, Forrester T (1975) The effect of curare on the release of acetylcholine from mammalian motor nerve terminals and an estimate of quantum content. J Physiol (Lond) 251:131–144Google Scholar
  69. Freeman SE, Turner RJ (1972) Agonist-antagonist interaction at the cholinergic receptor of denervated diaphragm. Aust J Exp Biol Med Sci 50:21–34PubMedGoogle Scholar
  70. Gage PW (1976) Generation of end-plate potentials. Physiol Rev 56:177–247PubMedGoogle Scholar
  71. Gage PW, Hamill OP (1981) Effects of anesthetics on ion channels in synapses. In: Porter R (ed) Neurophysiology IV. University Park Press, Baltimore (International Review of Physiology vol 25)Google Scholar
  72. Gage PW, McBurney RN, Van Helden D (1978) Octanol reduces end-plate channel lifetime. J Physiol (Lond) 274:279–298Google Scholar
  73. Gardner P, Ogden DC, Colquhoun D (1984) Conductances of single ion channels opened by cholinominetic agonists are indistinguishable. Nature 309:160–162PubMedGoogle Scholar
  74. Ginsborg BL, Jenkinson DH (1976) Transmission of impulses from nerve to muscle. In: Zaimis E (ed) Neuromuscular junction. Springer, Berlin Heidelberg New York, pp 229–364 (Handbuch der experimentellen Pharmakologie, vol 42)Google Scholar
  75. Ginsborg BL, Stephenson RP (1974) On the simultaneous action of two competitive antagonists. Br J Pharmacol 51:287–300Google Scholar
  76. Grunhagen H-H, Changeux J-P (1977) Fast kinetic studies on the interaction of cholinergic agonists with the membrane-bound acetylcholine receptor from Torpedo marmorata as revealed by quinacrine fluorescence. Eur J Biochem 80:225–242PubMedGoogle Scholar
  77. Gurney AM, Rang HP (1984) The channel-blocking action of methonium compounds on rat submandibular ganglion cells. Br J Pharmacol 82:623–642PubMedGoogle Scholar
  78. Gutfreund H (1972) Enzymes: physical principles. Wiley, LondonGoogle Scholar
  79. Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100PubMedGoogle Scholar
  80. Hartzell HC, Kuffler SW, Yoshikami D (1975) Post-synaptic potentiation: interaction between quanta of acetylcholine at the skeletal neuromuscular synapse. J Physiol (Lond) 251:427–463Google Scholar
  81. Head SD (1983) Temperature and end-plate currents in rat diaphragm. J Physiol (Lond) 334:441–459Google Scholar
  82. Heidmann T, Changeux JP (1979 a) Fast kinetic studies on the interaction of fluorescent agonist with the membrane-bound acetylcholine receptor from Torpedo marmorata. Eur J Biochem 94:255–279PubMedGoogle Scholar
  83. Heidmann T, Changeux J-P (1979 b) Fast kinetic studies on the allosteric interactions between acetylcholine receptor and local anesthetic binding sites. Eur J Biochem 94:281–296PubMedGoogle Scholar
  84. Hill AV (1909) The mode of action of nicotine and curari determined by the form of the contraction curve and the method of temperature coefficients. J Physiol (Lond) 39:361–373Google Scholar
  85. Hille B, Campbell DT (1976) An improved vaseline gap voltage clamp for skeletal muscle fibre. J Gen Physiol 67:265–293PubMedGoogle Scholar
  86. Hodgkin AL, Horowicz P (1959) The influence of potassium and chloride ions on the membrane potential of single muscle fibres. J Physiol (Lond) 148:127–160Google Scholar
  87. Hutter OF, Padsha SM (1959) Effect of nitrate and other ions on the membrane resistance of frog skeletal muscle. J Physiol (Lond) 146:117–132Google Scholar
  88. Jack JJB, Noble D, Tsien RW (1975) Electric current flow in excitable cells. Clarendon, OxfordGoogle Scholar
  89. Jenkinson DH (1960) The antagonism between tubocurarine and substances which depolarize the motor end-plate. J Physiol (Lond) 152:309–324Google Scholar
  90. Jenkinson DH, Terrar DA (1973) Influence of chloride ions on changes in membrane potential during prolonged application of carbachol to frog skeletal muscle. Br J Pharmacol 47:363–376PubMedGoogle Scholar
  91. Jurss R, Prinz H, Maelicke A (1979) NBD-5-Acylcholine: Fluorescent analog of acetycho-line and agonist at the neuromuscular junction. Proc Natl Acad Sci USA 76:1064–1068PubMedGoogle Scholar
  92. Karlin A (1980) Molecular properties of nicotinic acetylcholine receptors. Cell Surf Rev 6:191–260Google Scholar
  93. Kasai M, Changeux J-P (1971) In vitro excitation of purified membrane fragments by cholinergic agonists. I Pharmacological properties of the excitable membrane fragments. J Membrane Biol 6:1–23Google Scholar
  94. Katz B (1966) Nerve muscle and synapse. McGraw-Hill, New YorkGoogle Scholar
  95. Katz B, Miledi R (1970) Membrane noise produced by acetylcholine. Nature 226:962–963PubMedGoogle Scholar
  96. Katz B, Miledi R (1972) The statistical nature of the acetylcholine potential and its molecular components. J Physiol (Lond) 224:665–699Google Scholar
  97. Katz B, Miledi R (1973) The binding of acetylcholine to receptors and its removal from the synaptic cleft. J Physiol (Lond) 231:549–574Google Scholar
  98. Katz B, Miledi R (1977) Transmitter leakage from motor nerve endings. Proc R Soc Lond [Biol] B196:59–72Google Scholar
  99. Katz B, Miledi R (1978) A re-examination of curare action at the motor end-plate. Proc R Soc Lond [Biol] B203:119–133Google Scholar
  100. Katz B, Thesleff S (1957) A study of the desensitization produced by acetylcholine at the motor end-plate. J Physiol [Lond] 138:63–80Google Scholar
  101. Kistler J, Stroud RM, Klymkowsky MW, Lalancette RA, Fairclough RH (1982) Structure and function of an acetylcholine receptor. Biophys J 37:371–383PubMedGoogle Scholar
  102. Kuffler SW, Yoshikami D (1975) The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetycholine at the neuromuscular synapse. J Physiol (Lond) 251:465–482Google Scholar
  103. Land BR, Salpeter EE, Salpeter MM (1980) Acetylcholine receptor site density affects the rising phase of miniature end-plate currents. Proc Natl Acad Sci USA 77:3736–3740PubMedGoogle Scholar
  104. Land BR, Salpeter EE, Salpeter MM (1981) Kinetic parameters for acetylcholine interaction in intact neuromuscular junction. Proc Natl Acad Sci USA 78:7200–7204PubMedGoogle Scholar
  105. Langmuir I (1918) The adsorption of gases on plane surfaces of glass, mica and platinum. J Am Chem Soc 40:1361–1402Google Scholar
  106. Lo MMS, Dolly JO, Barnard EA (1981) Molecular forms of the acetylcholine receptor from vertebrate muscles and Torpedo electric organ. Eur J Biochem 116:155–163PubMedGoogle Scholar
  107. Magazanik LG, Vyskocil F (1973) Desensitization at the motor end-plate. In: Rang HP (ed) Drug receptors. Macmillan, LondonGoogle Scholar
  108. Magleby KL, Pallotta BS (1981) A study of desensitization of acetylcholine receptors using nerve-released transmitter in the frog. J Physiol (Lond) 316:225–250Google Scholar
  109. Magleby KL, Stevens CF (1972) A quantitative description of end-plate currents. J Physiol (Lond) 223:173–197Google Scholar
  110. Magleby KL, Pallotta BS, Terrar DA (1981) The effect of (+)-tubocurarine on neuromuscular transmission during repetitive stimulation in the rat mouse and frog. J Physiol (Lond) 312:97–113Google Scholar
  111. Manalis RS (1977) Voltage-dependent effect of curare at the frog neuromuscular junction. Nature 267:366–368PubMedGoogle Scholar
  112. Marty A, Ascher P (1980) Les Modes d’action de la tubocurarine. In: La transmission neuromusculaire les mediateurs et le “milieu interieur”. Fondation Singer-Polignac. Masson, Paris, pp 89–100Google Scholar
  113. Matthews-Bellinger J, Salpeter MM (1978) Distribution of acetylcholine receptors at frog neuromuscular junctions with a discussion of some physiological implications. J Physiol (Lond) 279:197–213Google Scholar
  114. McIntyre AR, King RE (1943) Contraction of denervated muscle produced by d-tubocurarine. Science 97:516PubMedGoogle Scholar
  115. Neher E (1983) The charge carried by single channel currents of rat cultured muscle cells in the presence of local anaesthetics. J Physiol (Lond) 339:663–678Google Scholar
  116. Neher E, Sakmann B (1975) Voltage-dependence of drug-induced conductance in frog neuromuscular junction. Proc Nat Acad Sci USA 72:2140–2144PubMedGoogle Scholar
  117. Neher E, Sakmann B (1976) Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature 260:799–802PubMedGoogle Scholar
  118. Neher E, Steinbach JH (1978) Local anaesthetics transiently block currents through single acetylcholine-receptor channels. J Physiol (Lond) 277:153–176Google Scholar
  119. Neher E, Stevens CF (1977) Conductance fluctuations and ionic pores in membranes. Annu Rev Biophys Bioeng 6:345–381PubMedGoogle Scholar
  120. Nelson N, Anholt R, Lindstrom J, Montal M (1980) Reconstitution or purified acetylcholine receptors with functional ion channels in planar lipid bilayers. Proc Natl Acad Sci USA 77:3057–3061PubMedGoogle Scholar
  121. Neubig RR, Cohen JB (1979) Equilibrium binding of [3H]tubocurarine and [3H]acetylcholine by Torpedo postsynaptic membranes: stoichiometry and ligand interactions. Biochemistry 18:5464–5475PubMedGoogle Scholar
  122. Neubig RR, Cohen JB (1980) Permeability control by cholinergic receptors in Torpedo postsynaptic membranes: agonist dose-response relations measured at second and millisecond times. Biochemistry 19:2770–2779PubMedGoogle Scholar
  123. Noda M, Takahashi H, Tanabe T, Toyosato M, Furutani Y, Hirose T, Asai M, Inayama S, Miyata T, Noma S (1982) Primary structure of a-subunit precursor of Torpedo cali-fornica acetylcholine receptor deduced from cDNA sequence. Nature 299:793–797PubMedGoogle Scholar
  124. Ogden DC, Colquhoun D (1983) The efficacy of agonists at the frog neuromuscular junction studied with single channel recording. Pflügers Arch 399:246–248PubMedGoogle Scholar
  125. Ogden DC, Siegelbaum SA, Colquhoun D (1981) Block of acetylcholine-activated ion channels by an uncharged local anaesthetic. Nature 289:596–598PubMedGoogle Scholar
  126. Ogden DC, Siegelbaum SA, Colquhoun D (1986) Mechanisms of action of the uncharged local anaesthetic benzocaine (in preparation)Google Scholar
  127. Paton WDM, Rang HP (1965) The uptake of atropine and related drugs by intestinal smooth muscle of the guinea-pig in relation to acetylcholine receptors. Proc R Soc Lond B Biol Sci 163:1–44PubMedGoogle Scholar
  128. Paton WDM, Waud DR (1967) The margin of safety of neuromuscular transmission. J Physiol (Lond) 191:59–90Google Scholar
  129. Pennefather P, Quastel DMJ (1981) Relation between subsynaptic receptor blockade and response to quantal transmitter at the mouse neumuscular junction. J Gen Physiol 78:313–344PubMedGoogle Scholar
  130. Pennefather P, Quastel DMJ (1982) Modification of dose-response curves by effector blockade and uncompetitive antagonism. Mol Pharmacol 22:369–380PubMedGoogle Scholar
  131. Peper K, Bradley RJ, Dreyer F (1982) The acetylcholine receptor at the neuromuscular junction. Physiol Rev 62:1271–1340PubMedGoogle Scholar
  132. Quast U, Schimerlik MI, Raftery MA (1979) Ligand-induced changes in membrane-bound acetylcholine receptor observed by ethidium fluorescence. II Stopped flow studies with agonists and antagonists. Biochemistry 18:1891–1901PubMedGoogle Scholar
  133. Raftery MA, Hunkapiller MW, Strader CD, Hood LE (1980) Acetylcholine receptor: complex of homologous subunits. Science 208:1454–1457PubMedGoogle Scholar
  134. Rang HP (1982) The action of ganglion blocking drugs on the synaptic responses of rat submandibular ganglion cells. Br J Pharmacol 75:151–168PubMedGoogle Scholar
  135. Rang HP, Ritter JM (1969) A new kind of drug antagonism: evidence that agonists cause a molecular change in acetylcholine receptors. Mol Pharmacol 5:394–411PubMedGoogle Scholar
  136. Rang HP, Ritter JM (1970) On the mechanism of desensitization of cholinergic receptors. Mol Pharmacol 6:357–382PubMedGoogle Scholar
  137. Rosenberry TL (1979) Quantitative simulation of endplate currents at neuromuscular junctions based on their reaction of acetylcholine with acetylcholine receptor and acetylcholinesterase. Biophys J 26:263–290PubMedGoogle Scholar
  138. Ruff RL (1977) A quantitative analysis of local anaesthetic alteration of miniature end-plate currents and end-plate current fluctuations. J Physiol (Lond) 264:89–124Google Scholar
  139. Ruff RL (1982) The kinetics of local anaesthetic blockade of end-plate channels. Biophys J 37:625–631PubMedGoogle Scholar
  140. Sakmann B, Adams PR (1979) Biophysical aspects of agonist action at frog end-plate. In: Jacob J (ed) Advances in pharmacology and therapeutics, vol 1: Receptors. Pergamon, Oxford, pp 81–90Google Scholar
  141. Sakmann B, Neher E (1983) Single channel recording. Plenum, New YorkGoogle Scholar
  142. Sakmann B, Patlak J, Neher E (1980) Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist. Nature 286:71–73PubMedGoogle Scholar
  143. Schindler H, Quast U (1980) Functional acetylcholine receptor from Torpedo marmorata in planar membranes. Proc Natl Acad Sci USA 77:3052–3056PubMedGoogle Scholar
  144. Schild HO (1949) pAx and competitive drug antagonism. Br J Pharmacol 4:277–280Google Scholar
  145. Sheridan RE, Lester HA (1975) Relaxation measurements on the acetylcholine receptor. Proc Natl Acad Sci USA 72:3496–3500PubMedGoogle Scholar
  146. Sheridan RE, Lester HA (1977) Rates and equilibria at the acetylcholine receptor of Elec-trophorus electroplaques. J Gen Physiol 70:187–219PubMedGoogle Scholar
  147. Shorr RG, Lyddiatt A, Lo MMS, Dolly JO, Barnard EA (1981) Acetylcholine receptor from mammalian skeletal muscle. Oligomeric forms and their subunit structure. Eur J Biochem 116:143–153PubMedGoogle Scholar
  148. Sine S, Taylor P (1979) Functional consequences of agonist-mediated state transitions in the cholinergic receptor. Studies in cultured muscle cells. J Biol Chem 254:3315–3325PubMedGoogle Scholar
  149. Sine SM, Taylor P (1980) The relationship between agonist occupation and the permeability response of the cholinergic receptor revealed by bound cobra α-toxin. J Biol Chem 255:10144–10156PubMedGoogle Scholar
  150. Sine SM, Taylor P (1981) Relationship between reversible antagonist occupancy and the functional capacity of the acetylcholine receptor. J Biol Chem 256:6692–6699PubMedGoogle Scholar
  151. Sine SM, Taylor P (1982) Local anesthetics and histrionicotoxin are allosteric inhibitors of the acetylcholine receptor. J Biol Chem 257:8106–8114PubMedGoogle Scholar
  152. Steinbach AB (1968 a) Alteration by Xylocaine (lidocaine) and its derivatives of the time course of the end-plate potential. J Gen Physiol 52:144–161PubMedGoogle Scholar
  153. Steinbach AB (1968 b) A kinetic model for the action of Xylocaine on receptors for acetylcholine. J Gen Physiol 52:162–180PubMedGoogle Scholar
  154. Steinbach JH (1980) Activation of nicotinic acetylcholine receptors. Cell Surf Rev 6:119–156Google Scholar
  155. Stenlake JB (1979) Molecular interactions at the cholinergic receptor in neuromuscular blockade. Prog Med Chem 16:257–286PubMedGoogle Scholar
  156. Stenlake JB (1980) Neuromuscular blocking agents. In: Wolff ME (ed) Alfred Burger’s medicinal chemistry, 4th edn. Wiley-Interscience. New YorkGoogle Scholar
  157. Stephenson RP (1956) A modification of receptor theory. Br J Pharmacol 11:379–393Google Scholar
  158. Suarez-Kurtz G, Paulo LG, Fonteies MC (1969) Further studies on the neuromuscular effects of β-diethylaminoethyl-diphenylpropylacetate hydrochloride (SKF-525-A). Arch Int Pharmacodyn 177:185–195PubMedGoogle Scholar
  159. Sugal N, Hughes R, Payne JP (1975) The effect of suxamethonium alone and its interaction with gallamine on the indirectly elicited tetanic and single twitch contractions of skeletal muscle in man during anaesthesia. Br J Clin Pharmacol 2:391–402Google Scholar
  160. Sugiyama H, Popot JL, Changeux JP (1976) Studies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ. III Pharmacological desensitization in vitro of the receptor-rich membrane fragments by cholinergic agonists. J Mol Biol 106:485–496PubMedGoogle Scholar
  161. Sumikawa K, Barnard EA, Dolly Jo (1982 a) Similarity of acetylcholine receptors of dener-vated, innervated and embryonic chicken muscles. Subunit compositions. Eur J Bio-chem 126:473–479Google Scholar
  162. Sumikawa K, Houghton M, Smith JC, Bell L, Richards BM, Barnard EA (1982 b) The molecular cloning and characterization of cDNA coding for the a subunit of the acetylcholine receptor. Nucleic Acids Res 10:5809–5822PubMedGoogle Scholar
  163. Takeuchi A, Takeuchi N (1960) The permeability of end-plate membrane during the action of transmitter. J Physiol (Lond) 154:52–67Google Scholar
  164. Terrar DA (1974) Influence of SKF-525A congeners, strophanthidin and tissue-culture media on desensitization in frog skeletal muscle. Br J Pharmacol 51:259–268PubMedGoogle Scholar
  165. Thesleff S (1955) The mode of neuromuscular block caused by acetylcholine, nicotine, de-camethonium and succinylcholine. Acta Physiol Scand 34:218–231Google Scholar
  166. Thron CD (1973) On the analysis of pharmacological experiments in terms of an allosteric receptor model. Mol Pharmacol 9:1–9PubMedGoogle Scholar
  167. Trautmann A (1982) Curare can open and block ionic channels associated with cholinergic receptors. Nature 298:272–275PubMedGoogle Scholar
  168. Tyer MB (1978) Factors limiting the rate of termination of the neuromuscular blocking action of fazadinium dibromide. Br J Pharmacol 63:287–293Google Scholar
  169. Tzartos SJ, Lindstrom JM (1980) Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci USA 77:755–759PubMedGoogle Scholar
  170. Van Maanen EF (1950) The antagonism between acetylcholine and the curare alkaloids D-tubocurarine, c-curarine-I, c-toxiferine-II and β-erythroidine in the rectus abdominis of the frog. J Pharmacol Exp Ther 99:255–264Google Scholar
  171. Wathey JC, Nass WM, Lester HA (1979) Numerical reconstruction of the quantal event at nicotinic synapses. Biophys J 27:145–164PubMedGoogle Scholar
  172. Waud BE, Cheng MC, Waud DR (1973) Comparison of drug-receptor dissociation constants at the mammalian neuromuscular junction in the presence and absence of hal-othane. J Pharmacol Exp Ther 187:40–46PubMedGoogle Scholar
  173. Waud DR (1967) The rate of action of competitive neuromuscular blocking agents. J Pharmacol Exp Ther 158:99–114PubMedGoogle Scholar
  174. Weber M, Changeux J-P (1974) Binding of Naja nigricollis 3H-α-toxin to membrane fragments from Electrophorus and Torpedo electric organs. 2 Effect of cholinergic agonists and antagonists on the binding of the tritiated α-neurotoxin. Mol Pharmacol 10:15–34PubMedGoogle Scholar
  175. Weber M, David-Pfeuty T, Changeux J-P (1975) Regulation of binding properties of the nicotinic receptor protein by cholinergic ligands in membrane fragments from Torpedo marmorata. Proc Natl Acad Sci USA 72:3443–3447PubMedGoogle Scholar
  176. Weiland G, Taylor P (1979) Ligand specificity of state transitions in the cholinergic receptor: behaviour of agonists and antagonists. Mol Pharmacol 15:197–212PubMedGoogle Scholar
  177. Weiland G, Georgia B, Lappi S, Chignell CF, Taylor P (1977) Kinetics of agonist-mediated transitions in state of the cholinergic receptor. J Biol Chem 25:7648–7656Google Scholar
  178. Wray D (1980) Noise analysis and channels at the postsynaptic membrane of skeletal muscle. Prog Drug Res 24:9–56PubMedGoogle Scholar
  179. Wray D (1981) Prolonged exposure to acetylcholine: noise analysis and channel inactiva-tion in cat tenuissimus muscle. J Physiol (Lond) 310:37–56Google Scholar
  180. Young AP, Sigman DS (1981) Allosteric effects of volatile anesthetics on the membrane-bound acetylcholine receptor protein. I Stabilization of the high affinity state. Mol Pharmacol 20:498–505PubMedGoogle Scholar
  181. Young AP, Sigman DS (1983) Conformational effects of volatile anesthetics on the membrane-bound acetylcholine receptor protein: facilitation of the agonist-induced affinity conversion. Biochemistry 22:2155–2162PubMedGoogle Scholar
  182. Zaimis E (1976) The neuromuscular junction: areas of uncertainty. In: Zaimis E (ed) Neuromuscular junction. Springer, Berlin Heidelberg New York, pp 1–21 (Handbuch der experimentellen Pharmakologie, vol 42)Google Scholar
  183. Zaimis E, Head S (1976) Depolarising neuromuscular blocking agents. In: Zaimis E (ed) Neuromuscular junction. Springer, Berlin Heidelberg New York, pp 365–419 (Handbook of experimental pharmacology, vol 42)Google Scholar
  184. Ziskind L, Dennis MJ (1978) Depolarising effect of curare on embryonic rat muscles. Nature 276:622–623PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1986

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  • D. Colquhoun

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