title: Inhibition of ionotropic neurotransmitter receptors by antagonists: strategy to estimate the association and the dissociation rate constant of antagonists with very strong affinity to the receptors.
abstract: Since binding of an agonist to an ionotropic neurotransmitter receptor causes not only channel opening, but also desensitization of the receptor, inhibition of the receptor by the antagonist sometimes becomes very complicated. The transient state kinetics of ligand association and dissociation, and desensitization of the receptor were considered on the basis of the minimal model proposed by Hess' group, and the following possibilities were proposed. 1) When an agonist is simultaneously applied to the receptor with an antagonist whose affinity to the receptor is extremely strong and different from that of the agonist, it is usually impossible to estimate the real inhibition constant exactly from the responses because desensitization of the receptor proceeds before the equilibrium of the ligand binding. Simultaneous addition of the antagonist with strong affinity to the receptor may apparently accelerate inactivation (desensitization) of the receptor. The association rate constant of the antagonist can be estimated by analyses of the rate of the inactivation in the presence and the absence of the antagonist. 2) A preincubated antagonist with a slow dissociation rate constant, i.e., a very effective inhibitor, may cause apparent noncompetitive inhibition of the receptor, since the receptor is desensitized by an agonist as soon as the antagonist dissociates from the receptor and the dissociation of the antagonist from the receptor becomes the rate-determining step. A nicotinic acetylcholine receptor (nAChR) was expressed in Xenopus oocytes by injecting mRNA prepared from Electrophorus electricus electroplax and used for the experiments on inhibition by an antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Chemistry, Faculty of Liberal Arts, Yamaguchi University.
authors.forename: H
authors.initials: H
authors.lastname: Aoshima
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Hori
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D005260:Female; D005703:Gallamine Triethiodide / Q000378:metabolism / Q000494:pharmacology; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008432:Mathematical Computing; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010197:Pancuronium / Q000378:metabolism / Q000494:pharmacology; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D013331:Strychnine / Q000494:pharmacology; D013997:Time Factors; D014403:Tubocurarine / Q000378:metabolism / Q000494:pharmacology; D014981:Xenopus / Q000502:physiology
chemical_list: D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D013331:Strychnine; D010197:Pancuronium; D000109:Acetylcholine; D005703:Gallamine Triethiodide; D014403:Tubocurarine