Receptor Blockade and Synaptic Function

  • D. M. J. Quastel
  • P. Pennefather
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 18)


When a neurotransmitter substance is released into a synaptic cleft it acts upon subsynaptic receptors to induce a response of the target cell and also interacts with systems which act to remove the substance. At no time is there an equilibrium, and it is inappropriate to apply equilibrium kinetics to predict the consequences of modifying the system, e.g. by blocking receptors. A mathematical model predicts that the subsynaptic response to each package or “quantum” of transmitter may be insensitive to competitive receptor blockade, or to quite large changes in receptor density, provided the density of receptors is normally enough for efficient capture of transmitter. This prediction is borne out by experimental data from the voltage-clamped mouse neuromuscular junction; it requires blockade or removal of about 80% of receptors (90% after poisoning of acetylcholinesterase) to reduce the miniature end-plate current, i.e. the action of a quantum if nerve-released acetylcholine (ACh), by 50%. On the other hand, drugs that interfere with receptor function without preventing ACh binding to receptors can be just as (or more) effective in blocking nerve-applied as in blocking exogenously applied transmitter substances. At the neuromuscular junction this is seen with receptor desensitization, and “non-specific” agents such as local and general anaesthetics. We conclude that care must be taken in extrapolating from data re receptor number and/or occupancy by blocking drugs to consequences in terms of synaptic function.


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  1. Adams, P.R.: A model for the procaine end-plate current. J. Physiol. (Lond.) 246, 61–63 (1975).Google Scholar
  2. Colquhoun, D., Dreyer, F., Sheridan, E.: The actions of tubocurarine at the frog neuromuscular junction. J. Physiol. (Lond.) 266, 361–395 (1979).CrossRefGoogle Scholar
  3. Dreyer, F., Peper, K., Sterz. R.: Determination of dose response curves by quantitations iontophoresis at the frog neuromuscular junction. J. Physiol. (Lond.) 281, 421–444 (1978).CrossRefGoogle Scholar
  4. Elmgvist, D., Hofmann, W. W, Kugelberg, j, Quastel D. MI: An electrophysiological investigation of neuromuscular transmission in myasthenia gravis. J. Physiol. (Lond.) 174, 417–434 (1964).CrossRefGoogle Scholar
  5. Fambrough, D. M., Hartzell, H. C.: Acetylcholine receptors: number and distribution at neuromuscular junctions in rat diaphragm. Science (N.Y.) 176, 189–191 (1972).CrossRefGoogle Scholar
  6. Feltz, A., Trautmann, A.: Desensitization at the frog neuromuscular junction: a biphasic process. J. Physiol. (Lond.) 322, 257–272 (1982).CrossRefGoogle Scholar
  7. Fertuck, H. C., Salpeter, M. M.: Localization of acetylcholine receptor by 1zsI labelled a-bungarotoxin binding at mouse motor endplate. Proc. Natl. Acad. Sci., U.S.A. 71, 1376–1378 (1974).CrossRefPubMedCentralPubMedGoogle Scholar
  8. Fertuck, H. C., Salpeter, M. M.: Quantitation of junctional and extra-junctional acetylcholine receptors by electron microscope autoradiography after 121-a-bungarotoxin binding at mouse neuromuscular junctions. J. Cell. Biol. 69, 144–158 (1976).CrossRefPubMedCentralPubMedGoogle Scholar
  9. Gage, P. W, McBurney, R. N, Schneider, G. T.: Effects of some aliphatic alcohols on the conductance change caused by a quantum of acetylcholine at the toad endplate. J. Physiol. (Lond.) 244, 409–429 (1975).CrossRefGoogle Scholar
  10. Hartzell H. C., Kugler, S. W, Yoshikami, D.: Post-synaptic potentiation: interaction between quanta of acetylcholine at the skeletal neuromuscular synapse. J. Physiol. (Lond.) 152, 309–324 (1975).Google Scholar
  11. Katz B., Miledi, R.: The binding of acetylcholine in receptors and its removal from the synaptic cleft. J. Physiol. (Lond.) 231, 549–574 (1973).CrossRefPubMedCentralGoogle Scholar
  12. Katz, B., Thesleff S.: A study of the desensitization produced by acetylcholine at the motor end-plate. J. Physiol. (Lond.) 138, 60–80 (1957).CrossRefGoogle Scholar
  13. Pennefather, P., Quastel, D. M.J.: The effects of myasthenic IgG on miniature end-plate currents in mouse diaphragm. Life Sci. 27, 2047–2054 (1980 a).Google Scholar
  14. Pennefather, P., Quastel, D. M.J.: Actions of Anesthetics on the function of nicotinic acetylcholine receptors. In: Progress in Anesthesiology, Vol. 2: Molecular Mechanisms of Anesthetics (Fink, B. R., ed.), pp. 157–168. New York: Raven Press. 1980 b.Google Scholar
  15. Pennefather, P., Quastel, D. M.J.: Relation between subsynaptic receptor blockade and response to quantal transmitter at the mouse neuromuscular junction. J. Gen. Physiol. 78, 313–344 (1981).CrossRefPubMedGoogle Scholar
  16. Pennefather, P., Quastel, D. M.J.: Modifications of dose-response curves by effector blockade and uncompetitive antagonism. Molec. Pharmacol. 22, 369–380 (1982).Google Scholar
  17. Quastel, D. M.J., Linder, T. M.: Pre- and post-synaptic actions of central depressants at the mammalian neuromuscular junction. In: Progress in Anesthesiology, Vol. 1: Molecular Mechanisms of Anaesthesia (Fink, B. R., ed.), pp. 157–168. New York: Raven Press. 1975.Google Scholar
  18. Richter, J., Landau, E. M., Cohen, S.: The action of volatile anesthetics and convulsants on synaptic transmission: A unified concept. Molec. Pharmacol. 13, 548–559 (1977 a).Google Scholar
  19. Richter, J., Landau, E. M., Cohen, S.: Effect of fluorinated ethers on channel conductance in a cholinergic synapse. Isr. J. Med. Sci. 13, 533–534 (1977 b).Google Scholar
  20. Wathey, J. C., Nass, W. M., Lester, H. A.: Numerical reconstruction of the quantal event at nicotinic synapses. Biophys. J. 27, 145–164 (1979).CrossRefPubMedCentralPubMedGoogle Scholar
  21. Authors’ address: Prof. Dr. D. Quastel, Department of Pharmacology, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, B.C., Canada V6T 1W5.Google Scholar

Copyright information

© Springer-Verlag Wien 1983

Authors and Affiliations

  • D. M. J. Quastel
    • 1
  • P. Pennefather
    • 2
  1. 1.Department of PharmacologyThe University of British ColumbiaVancouverCanada
  2. 2.Department of Pharmacology, Faculty of MedicineThe University of British ColumbiaVancouverCanada

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