Vulnerability of desensitized or curare-treated acetylcholine receptors to irreversible blockade by cobra toxin

Abstract

Inactivation of frog myoneural acetylcholine receptors by cobra toxin (24-120 nM) is studied in the presence of reversible antagonists (d-tubocurarine, dihydro-β-erythroidine) and agonists (carbachol, nicotine). During agonist treatments most receptors are densensitized rather than activated. Neither agonists nor antagonists reverse the blockade produced by the toxin. At 26 µM d-tubocurarine, receptors are partially protected from the toxin. At 5 µM d-tubocurarine, a concentration which blocks 97% of the receptors, or lower concentrations, curare-blocked and free receptors are equally vulnerable to the toxin. Receptors are protected against the toxin at 7-140 µM carbachol, concentrations which desensitize 60-99.6% of the receptors. During combined treatment with agonist and toxin, end plate potential amplitudes decline in 300-600 sec to an irreversible "plateau" rather than exponentially to zero. The plateau is well described, as a very slow decline in the number of available receptors, by the following scheme. (A) The receptor population undergoes three simultaneous processes with first-order rate constants in the range 10-4 to 10-2 sec-1: reversible desensitization by agonists, recovery from desensitization, and irreversible inactivation by toxin. (B) Desensitized receptors are essentially invulnerable to the toxin. The agonist data are consistent with the model for desensitization proposed by Katz and Thesleff [J. Physiol. (London) 138, 63 (1957)].

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