Molecular Interactions of Organophosphates (OPs), Oximes and Carbamates at Nicotinic Receptors

  • Edson X. Albuquerque
  • Manickavasagom Alkondon
  • Sharad S. Deshpande
  • Vanga K. Reddy
  • Yasco Aracava


The nicotinic acetylcholine receptor-ion channel macromolecule (AChR), which is densely distributed at the endplate region of skeletal muscle and in Torpedo electric organ, is the best characterized among agonist-gated ion channels (Karlin, 1980; Spivak and Albuquerque, 1982; Noda et al., 1983; Changeux et al., 1984; Sakmann et al., 1985). This molecule comprises the neurotransmitter recognition site and the ion channel and is formed by five polypeptide subunits α, β, γ, and δ with a stoichiometry of 2:1:1:1. The subunits of the ion channel traverse the mem­brane and protrude about 50 Å towards the extracellular side and 15 Å towards the interior side of the cell membrane (Ross et al., 1977; Klymkowsky et al., 1980).


Channel Blockade Single Channel Current Organophosphate Poisoning Desensitize State Endplate Current 
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  1. Adler, M., Albuquerque, E.X. and Lebeda, F.J., 1978, Kinetic analysis of endplate currents altered by atropine and scopolamine, Mol. Pharmacol., 14: 514–529.Google Scholar
  2. Aguayo, L.G. and Albuquerque, E.X., 1986, The voltage— and time—dependent effects of phencyclidines on the endplate currents arise from open and closed channel blockade, Proc. Natl. Acad. Sci. USA, 83: 3523–3527.Google Scholar
  3. Albuquerque, E.X., Aracava, Y., Cintra, W.M., Brossi, A., Schönenberger, B. and Deshpande, S.S., 1988a, Structure—activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospecificity of nicotinic acetylcholine receptor—ion channel complex, Brazilian J. Med. Biol., Res., 21: 1173–1196.Google Scholar
  4. Albuquerque, E.X., Aracava, U., Idriss, M., Schönenberger, B., Brossi, A. and Deshpande, S.S., 1987, Activation and blockade of the nicotinic and glutamatergic synapses by reversible and irreversible cholinesterase inhibitors, in: “Neurobiology of Acetylcholine,” N.J. Dun and R.L. Perlman, eds., pp. 301–328, Plenum Publ. Corp., New York, NY.Google Scholar
  5. Albuquerque, E.X., Daly, J.W. and Warnick, J.E., 1988b, Macromolecular sites for specific neurotoxins and drugs on chemosensitive synapses and electrical excitation in biological membranes, in: “Ion Channels,” T. Narahashi, ed., Vol. I, pp. 95–162, Plenum Publ. Corp., New York, NY.Google Scholar
  6. Albuquerque, E.X., Deshpande, S.S., Kawabuchi, M., Aracava, Y., Idriss, M., Rickett, D.L. and Boyne, A.F., 1985, Multiple actions of anticholinesterase agents on chemosensitive synapses: Molecular basis for prophylaxis and treatment of organophosphate poisoning, Fundam. Appl. Toxicol., 5: S182 — S203.CrossRefGoogle Scholar
  7. Albuquerque, E.X., Kuba, K., and Daly, J., 1974, Effect of histrionicotoxin on the ionic conductance modulator of the cholinergic receptor: A quantitative analysis of the endplate current, J. Pharmacol. Exp. Ther., 189: 513–524.Google Scholar
  8. Alkondon, M. and Albuquerque, E.X., 1988, Non—oxime bispyridinium compound SAD-128 alters the kinetics of ACh—activated channels, Neurosci. Abs., 14: 640.Google Scholar
  9. Alkondon, M. and Rao, K.S. and Albuquerque, E.X., 1988, Acetylcholinesterase reactivators modify the functional properties of the nicotinic acetylcholine receptor ion channel, J. Pharmacol. Exp. Ther., 245: 543–556.Google Scholar
  10. Allen, C.N., Akaike, A. and Albuquerque, E.X., 1984, The frog interosseal muscle fiber as a new model for patch clamp studies of chemosensitive and voltage—sensitive ion channels, J. Physiol. ( Paris ), 79: 338–343.Google Scholar
  11. Anderson, C.R. and Stevens, C.F., 1973, Voltage clamp analysis of acetylcholine produced end—plate current fluctuations at frog neuromuscular junction, J. Physiol. ( Lond. ), 236: 655–691.Google Scholar
  12. Aracava, Y., Deshpande, S.S., Rickett, D.L., Brossi, A., Schönenberger, B. and Albuquerque, E.X., 1987, The molecular basis of anticholinesterase actions on nicotinic and glutamatergic synapses, in: “Myasthenia Gravis: Biology and Treatment,” D.B. Drachman, ed., Ann. N.Y. Acad. Sci., 505: 226–255.Google Scholar
  13. Aracava, Y., Ikeda, S.R., Daly, J.W., Brookes, N., and Albuquerque, E.X., 1984, Interactions of bupivacaine with ionic channels of the nicotinic receptor, Analysis of single channel currents, Mol. Pharmacol., 26: 304–313.Google Scholar
  14. Changeux, J.—P., Devillers—Thiéry, A. and Chemouilli, P., 1984, Acetylcholine receptor: an allosteric protein, Science, 225: 1335–1345.PubMedCrossRefGoogle Scholar
  15. Clement, J.G., 1981, Toxicology and pharmacology of bispyridinium oximesinsight into the mechanism of action vs soman poisoning in vivo, Fundam. Appl. Toxicol., 1: 193–202.Google Scholar
  16. Colquhoun, D. and Sakmann, B., 1981, Fluctuations in the microsecond time range of the current through single acetylcholine receptor ion channels, Nature (Lond.), 294: 464–466.CrossRefGoogle Scholar
  17. Deshpande, S.S., Viana, G.B., Kauffman, F.C., Rickett, D.L. and Albuquerque, E.X., 1986, Effectiveness of physostigmine as a pretreatment drug for protection of rats from organophosphate poisoning, Fundam. Appl. Toxicol., 6: 566–577.Google Scholar
  18. Eldefrawi, M.E., Schweizer, G., Bakry, N.M. and Valdes, J.J., 1988, Desensitization of the nicotinic acetylcholine receptor by diisopropylfluorophosphate, J. Biochem. Toxicol., 3: 21–32.Google Scholar
  19. Feltz, A., and Trautmann, A., 1982, Desensitization at the frog neuromuscular junction: A biphasic process, J. Physiol. (Lond.), 322: 257–272.Google Scholar
  20. Hamill, O.P., Marty, A., Neher, E., Sakmann, B. and Sigworth, F.J., 1981, Improved patch—clamp techniques for high—resolution current recording from cells and cell—free membrane patches, Pflügers Arch., 391: 85–100.PubMedCrossRefGoogle Scholar
  21. Heidmann, T. and Changeux, J.—P., 1978, Structural and functional properties of the acetylcholine receptor protein in its purified and membrane bound states, Ann. Rev. Biochem., 47: 317–357.Google Scholar
  22. Heidmann, T. and Changeux, J.—P., 1980, Interaction of fluorescent agonist with the membrane—bound acetylcholine receptor from Torpedo marmorata in the millisecond time range: Resolution of an “intermediate” conformational transition and evidence for positive cooperative effects, Biochem. Biophys. Res. Commun., 97: 889–896.Google Scholar
  23. Idriss, M.K., Aguayo, L.G., Rickett, D.L. and Albuquerque, E.X., 1986, Organophosphate and carbamate compounds have pre— and postjunctional effects at the insect glutamatergic synapse, J. Pharmacol. Exp. Ther., 239: 279–285.Google Scholar
  24. Ikeda, S.R., Aronstam, R.S., Daly, J.W., Aracava, Y. and Albuquerque, E.X., 1984, Interactions of bupivacaine with ionic channels of the nicotinic receptor. Electrophysiological and biochemical studies, Mol. Pharmacol. 26: 293–303.Google Scholar
  25. Karlin, A., 1980, Molecular properties of nicotinic acetylcholine receptor, in: “The Cell Surface and Neuronal Function,” C.W. Cotman, G. Poste and G.L. Nicolson, eds., pp. 191–260, Elsevier North Holland Biomedical Press, Amsterdam.Google Scholar
  26. Katz, B. and Miledi, R., 1973, The characteristics of `endplate noise’ produced by different depolarizing drugs, J. Physiol. ( Lond. ), 230: 707–717.Google Scholar
  27. Katz, B. and Thesleff, S., 1957, A study of the `desensitization’ produced by acetylcholine at the motor endplate, J. Physiol. ( Lond. ), 138: 63–80.Google Scholar
  28. Kawabuchi, M., Boyne, A.F., Deshpande, S.S. and Albuquerque, E.X., 1986, Comparison of the endplate myopathy induced by two different carbamates in rat soleus muscle, Neurosci. Abs., 12: 740.Google Scholar
  29. Kawabuchi, M., Boyne, A.F., Deshpande, S.S., Cintra, W.M., Brossi, A. and Albuquerque, E.X., 1988, Enantiomer (+)physostigmine prevents organophosphate—induced sub junctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation, Synapse, 2: 139–147.Google Scholar
  30. Kawabuchi, M., Boyne, A.F., Deshpande, S.S., and Albuquerque, E.X., 1989, The reversible carbamate, (—) physostigmine, reduces the size of synaptic endplate lesions induced by sarin, an irreversible organophosphate, Toxicol. & Appl. Pharmacol., 97: 98–106.CrossRefGoogle Scholar
  31. Klymkowsky, M., Heuser, J.E., and Stroud, R.M., 1980, Protease effects on the structure of acetylcholine receptor membranes from Torpedo californica, J. Cell Biol., 85: 823–838.PubMedCrossRefGoogle Scholar
  32. Kuba, K., Albuquerque, E.X., Daly, J., and Barnard, E.A., 1974, A study of the irreversible cholinesterase inhibitor, diisopropylfluorophosphate on time course of endplate currents in frog sartorius muscle, J. Pharmacol. Exp. Ther., 193: 232–245.Google Scholar
  33. Lapa, A.J., Albuquerque, E.X. and Daly, J., 1974, An electrophysiological study of the effects of d—tubocurarine, atropine, and a—bungarotoxin on the cholinergic receptor in innervated and chronically denervated mammalian skeletal muscles, Exp. Neurol., 43: 375–398.Google Scholar
  34. Lee, C.Y., 1972, Chemistry and pharmacology of polypeptide toxins in snake venoms, Ann. Rev. Pharmacol., 12: 265–286.Google Scholar
  35. Magleby, K.L. and Stevens, C.F., 1972, A quantitative description of end—plate currents, J. Physiol. ( Lond. ), 233: 173–197.Google Scholar
  36. Meshul, C.K., Boyne, A.F., Deshpande, S.S. and Albuquerque, E.X., 1985, Comparison of the ultrastructural myopathy induced by anticholinesterase agents at the end plates of rat soleus and extensor muscle, Exp. Neurol., 89: 96–114.Google Scholar
  37. Neher, E. and Sakmann, B., 1976, Single channel currents recorded from membrane of denervated frog muscle fibers, Nature (Lond.), 260: 799–802.CrossRefGoogle Scholar
  38. Neher, E. and Steinbach, J.H., 1978, Local anesthetics transiently block currents through single acetylcholine receptor channels, J. Physiol. ( Lond. ), 277: 153–176.Google Scholar
  39. Noda, M., Furutani, Y., Takahashi, H., Toyosato, M., Tanabe, T., Shimizu, S., Kikyotani, S., Kayano, T., Hirose, T., Inayama, S., Miyata, T. and Numa, S., 1983, Cloning and sequence analysis of calf cDNA and human genomic DNA encoding a—subunit precursor of muscle acetylcholine receptor, Nature (Lond.), 305: 818–823.CrossRefGoogle Scholar
  40. Oldiges, H., 1976, Comparative studies of the protective effects of pyridinium compounds against organophosphate poisoning, in: “Medical Protection Against Chemical Warfare Agents,” J. Stares, ed., pp. 101–108, SIPRI Books, Almqvist and Wiksells, Stockholm.Google Scholar
  41. Oldiges, H., and Schoene, K., 1970, Pyridinium and imidazolium salts as antidotes for soman and paraoxon poisoning in mice, Arch. Toxicol., 26: 293–305.Google Scholar
  42. Reddy, F.K., Deshpande, S.S. and Albuquerque, E.X., 1987, Bispyridinium oxime HI-6 reverses organophosphate ( OP)—induced neuromuscular depression in rat skeletal muscle, Fed. Proc., 46: 862.Google Scholar
  43. Rao, K.S., Aracava, Y., Rickett, D.L. and Albuquerque, E.X., 1987, Noncompetitive blockade of the nicotinic acetylcholine receptor—ion channel complex by an irreversible cholinesterase inhibitor, J. Pharmacol. Exp. Ther., 240: 337–344.Google Scholar
  44. Rao, K.S., Alkondon, M., Aracava, Y. and Albuquerque, E.X., 1986, A comparative study of organophosphorus compounds on frog neuromuscular transmission, Neurosci. Abs., 12: 739.Google Scholar
  45. Ross, M.J., Klymkowsky, M.W., Agard, D.A., and Stroud, R.M., 1977, Structural studies of a membrane—bound acetylcholine receptor from Torpedo californica, J. Mol. Biol., 116: 645–659.Google Scholar
  46. Ruff, R.L., 1977, A quantitative analysis of local anaesthetic alteration of miniature end—plate current fluctuations, J. Physiol. ( Lond. ), 264: 89–124.Google Scholar
  47. Sakmann, B., Methfessel, C., Mishina, M., Takahashi, T., Takai, T., Kurasaki, M., Fukuda, K. and Numa, S., 1985, Role of acetylcholine receptor subunits in gating of the channel, J. Physiol. ( Lond. ), 318: 538–543.Google Scholar
  48. Sakmann, B., Patlak, J., and Neher, E., 1980, Single acetylcholine—activated channels show burst—kinetics in presence of desensitizing concentrations of agonists, Nature (Lond.), 286: 71–73.CrossRefGoogle Scholar
  49. Shaw, K.—P., Aracava, Y., Akaike, A., Daly, J.W., Rickett, D.L. and Albuquerque, E.X., 1985, The reversible cholinesterase inhibitor physostigmine has channel—blocking and agonist effects on the acetylcholine receptor—ion channel complex, Mol. Pharmacol., 28: 527–538.Google Scholar
  50. Spivak, C.E. and Albuquerque, E.X., 1982, Dynamic properties of the nicotinic acetylcholine receptor ionic channel complex: activation and blockade. in: “Progress in Cholinergic Biology: Model Cholinergic Synapses,” I. Hanin and A.M. Goldberg, eds., pp. 323–357, Raven Press, New York, NY.Google Scholar
  51. Spivak, C.E., Maleque, M.A., Takahashi, K., Brossi, A. and Albuquerque, E.X., 1983, The ionic channel of the nicotinic acetylcholine receptor is unable to differentiate between the optical antipodes of perhydrohistrionicotoxin, FEBS the nicotinic receptor, Mol. Pharmacol., 18:384–394.Google Scholar
  52. Spivak, C.E., Witkop, B., and Albuquerque, E.X., 1980, Anatoxin—A: A novel, potent agonist., 1968, A kinetic model for the action of xylocaine on receptors for acetylcholine, J. Gen. Phvsiol., 52: 162–180.Google Scholar
  53. Swanson, K.L., Allen, C.N., Aronstam, R.S., Rapoport, H. and Albuquerque, E.X., 1986, Molecular mechanisms of the potent and stereospecific nicotinic receptor agonist (+)—Anatoxin—a, Mol. Pharmacol., 29: 250–257.Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Edson X. Albuquerque
    • 1
    • 2
  • Manickavasagom Alkondon
    • 1
  • Sharad S. Deshpande
    • 1
  • Vanga K. Reddy
    • 1
  • Yasco Aracava
    • 1
    • 2
  1. 1.Department of Pharmacology and Experimental TherapeuticsUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Molecular Pharmacology Training Program Institute of Biophysics “Carlos Chagas Filho”Federal University of Rio de JaneiroRio de JaneiroBrazil

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