Modulation of nicotinic acetylcholine receptors by strychnine

Strychnine, a potent and selective antagonist at glycine receptors, was found to inhibit muscle (alpha(1)beta(1)gamma delta, alpha(1)beta(1)gamma, and alpha(1)beta(1)delta) and neuronal (alpha(2)beta(2) and alpha(2)beta(4)) nicotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes, Strychnine alone (up to 500 mu M) did not elicit membrane currents in oocytes expressing AcChoRs, but, when applied before, concomitantly, or during superfusion of acetylcholine (AcCho), it rapidly and reversibly inhibited the current elicited by AcCho (AcCho-current), Although in the three cases the AcCho-current was reduced to the same level, its recovery was slower when the oocytes were preincubated with strychnine, The amount of AcCho-current inhibition depended on the receptor subtype, and the order of blocking potency by strychnine was alpha(1)beta(1)gamma delta > alpha(2)beta(4) > alpha(2)beta(2). With the three forms of drug application, the Hill coefficient was close to one, suggesting a single site for the receptor interaction,vith strychnine, and this interaction appears to be noncompetitive. The inhibitory effects on muscle AcChoRs were voltage-independent, and the apparent dissociation constant for Ac-Cho was not appreciably changed by strychnine, In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependent, with an electrical distance of approximate to 0.35. We conclude that strychnine regulates reversibly and noncompetitively the embryonic type of muscle AcChoR and some forms of neuronal AcChoRs. In the former case, strychnine presumably inhibits allosterically the receptor by binding at an external domain whereas, in the latter case, it blocks the open receptor-channel complex.