Modulation of nicotinic acetylcholine receptors by strychnine

Strychnine, a potent and selective antagonist at glycine receptors, was fou nd 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)) n icotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes, St rychnine alone (up to 500 mu M) did not elicit membrane currents in oocytes expressing AcChoRs, but, when applied before, concomitantly, or during sup erfusion 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 t he oocytes were preincubated with strychnine, The amount of AcCho-current i nhibition depended on the receptor subtype, and the order of blocking poten cy 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 wa s close to one, suggesting a single site for the receptor interaction,vith strychnine, and this interaction appears to be noncompetitive. The inhibito ry effects on muscle AcChoRs were voltage-independent, and the apparent dis sociation constant for Ac-Cho was not appreciably changed by strychnine, In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependen t, with an electrical distance of approximate to 0.35. We conclude that str ychnine regulates reversibly and noncompetitively the embryonic type of mus cle AcChoR and some forms of neuronal AcChoRs. In the former case, strychni ne presumably inhibits allosterically the receptor by binding at an externa l domain whereas, in the latter case, it blocks the open receptor-channel c omplex.