Modulation of nicotinic acetylcholine receptors by strychnine.
Strychnine, a potent and selective antagonist at glycine receptors, was found to inhibit muscle (alpha1beta1gammadelta, alpha1beta1gamma, and alpha1beta1delta) and neuronal (alpha2beta2 and alpha2beta4) nicotinic acetylcholine receptors (AcChoRs) expressed in Xenopus oocytes. Strychnine alone (up to 500 microM) 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 alpha1beta1gammadelta > alpha2beta4 > alpha2beta2. With the three forms of drug application, the Hill coefficient was close to one, suggesting a single site for the receptor interaction with strychnine, and this interaction appears to be noncompetitive. The inhibitory effects on muscle AcChoRs were voltage-independent, and the apparent dissociation constant for AcCho was not appreciably changed by strychnine. In contrast, the inhibitory effects on neuronal AcChoRs were voltage-dependent, with an electrical distance of approximately 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.
García-Colunga
J
J
Centro de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Apartado Postal 1-1141, Juriquilla, Querétaro 76001, México.
Miledi
R
R
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018075:RNA, Complementary; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013331:Strychnine / Q000494:pharmacology*; D014982:Xenopus laevis
D046911:Macromolecular Substances; D018075:RNA, Complementary; D011978:Receptors, Nicotinic; D013331:Strychnine; D000109:Acetylcholine