The Blockade of Open Channel of Acetylcholine Receptor is Responsible for Selective Blockade of Nicotinic Transmission
Hexamethonium, a selective ganglionic blocker, at its lowest effective concentration exhibits the open-channel blockade of nicotinic acetylcholine (ACh) receptors in sympathetic ganglion neurones, with no signs of their competitive blockade. This is evidenced by the facts that 1) hexamethonium shortens in a voltage-dependent manner the apparent mean channel lifetime estimated from the excitatory postsynaptic current (EPSC) decay and from the ACh noise analysis as well as from the analysis of single channel activity, and 2) the hexamethonium-induced reduction of the ACh current amplitude is enhanced by the preliminary opening of the ACh-gated channels.
The rate constants that characterize binding of hexamethonium, pirilenum and some other selective ganglionic blockers to an open ACh-gated channel correlates with their ganglion-blocking activities, in contrast to what is observed in the effects of competitive ganglionic blockers tubocurarine and trimethaphan. This observation suggests that selective ganglionic blockade produced by some compounds is due to an open-channel blockade while in other cases it is due to a competitive mechanism. The selective blockade of open channel can be observed in different types of synapses. It is suggested that the site in the ACh-gated open channel that binds selective blockers normally binds Ca2+ ions.
KeywordsOpen Channel Sympathetic Ganglion Selective Blockade Single Channel Activity Nicotinic AChR
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- Ascher, P., Marty, A., and Neild, T.O., 1978a, Life-time and elementary conductance of the channels mediating the excitatory effects of acetylcholine in Aplysia neurones.Google Scholar
- Blackman, J.C., 1970, Dependence on membrane potential of the blocking action of hexamethonium at a sympathetic ganglionic synapse. Proc. Univ. Otago Med. Sch. 48: 4–5.Google Scholar
- Colquhoun, D., 1979, The link between drug binding and response: theories and observations, in: The Receptors. A Comprehensive Treatise. Ed. R.D. O’Brien, vol. 1: 93–141, Plenum Press, New York.Google Scholar
- Colquhoun, D., and Ogden, D.C., 1984, Evidence from single-channel recording of channel block by nicotinic agonists at the frog neuromuscular junction. J. Physiol. 353: 90 P.Google Scholar
- Colquhoun, D., and Sakmann, B., 1983, Bursts of openings in transmitter- activated ion channels, in: Single-Channel Recording, p. 345–364, Sakmann, B., and Neher, E., ed., Plennum Press, New York.Google Scholar
- Derkach, V.A., North, R.A., Selyanko, A.A., and Skok, V.I., 1986, Single channels activated by acetylcholine in rat cervical ganglion. In press.Google Scholar
- Grob, D., 1967, Neuromuscular blocking drugs, in: Physiological Pharmacology. III/C 389–460, Root, W.S., and Hofman, W.S., ed., Academic Press, New York.Google Scholar
- Hille, B., Courtney, K., and Dum, R., 1975, Rate and site of action of local anaesthetics in myelinated nerve fibres, in: Molec. mechanisms of Anaesthesia. Progress in Anesthesiology.Google Scholar
- Karlin, A., Cox, R., Kaldany, R.-R., Lober, P., and Holtzmanman, E., 1983, The arrangement and functions of the chains of the acetylcholine receptor of Torpedo electric tissue, in: Molecular Neurobiology. Cold Spring Harbor Symposia on Quantitative Biology. 48: 1–8.Google Scholar
- Magazanik, L.G., Antonov, S.M., and Gmiro, V.E., 1984. Kinetics and pharmacological blockade of glutamate-activated postsynaptic ion channels. Biol. Membr. 1: 130–140 (in Russ.)Google Scholar
- Marty, A., 1980, Action of calcium ions on acetylcholine-sensitive channels in Aplysia neurones. J. Physiol. 76:523–527, Paris.Google Scholar
- Paton, W.D.M., and Zaimis, E.J., 1949, The pharmacological actions of polymathylene bistrimethylammonium salts. Br. J. Pharmacol. 4: 381–400.Google Scholar
- Selyanko, A.A., Derkach, V.A., and Skok, V.I., 1981, Effects of some ganglion-blocking agents on fast excitatory postsynaptic currents in mammalian sympathetic ganglion neurones. in: Adv. Physiol. Sci. 4:329–342, Physiology of Excitable Membranes (ed. J. Salanki).Google Scholar
- Selyanko, A.A., Kerkach, V.A., and Skok, V.I., 1985, The effect of Ca2+ ions on the channel-blocking action of hexamethonium in sympathetic ganglion. Proceedings of the USSR Academy of Sciences. 284: 225–228, (in Russian).Google Scholar
- Sine, S.M., and Steinbach, J.H., 1984, Agonists block currents through acetylcholine receptor channels. Bio. Phys. J., 46: 277–283.Google Scholar
- Skok, V.1., Selyanko, A.A., Derkach, V.A., Gmiro, V.E., and Lukomskaya, N.Ya., 1984, The mechanisms of ganglion-blocking action of bisammonium compounds. Neirophysiology, 16: 46–52.Google Scholar
- Vladimirova, I.A., and Shuba, M.F., 1978, Strychnine, hydrastine and apamin effect on synaptic transmission in smooth muscle cells. Neirophysiology, 10: 295–299.Google Scholar