CHLORPYRIFOS, PARATHION, AND THEIR OXONS BIND TO AND DESENSITIZE A NICOTINIC ACETYLCHOLINE-RECEPTOR - RELEVANCE TO THEIR TOXICITIES

The nicotinic acetylcholine receptor (nAChR) of the electric organ of the electric ray, Torpedo sp., the richest source of nAChR, with simil ar structure and pharmacology to the mammalian skeletal muscle nAChR, carries several binding sites for different ligands, Incubation of Tor pedo membrane-bound nAChRs with the agonist carbamylcholine (Carb) sti mulated the binding of [H-3]-thienyl-cyclohexylpiperidine ([H-3]TCP), which binds to the receptor's noncompetitive antagonist binding site i n its ionic channel, with high affinity (K-d Of 196 nM). The agonist-s timulated binding of [H-3]TCP (i.e., binding to activated nAChRs) was inhibited in a concentration-dependent manner by four organophosphate (OF) anticholinesterases, chlorpyrifos oxon (CPO), chlorpyrifos (CPS), parathion (PS), and paraoxon (PO) with IC50 (concentration that inhib its 50% of the effect) values of 5, 150, 200, and 300 mu M, respective ly, The binding of CPO was totally reversible, The OPs had no effect o n equilibrium binding of [alpha-I-125]bungarotoxin ([alpha-(125) I]BGT ) to the receptor's acetylcholine (ACh)-binding site, but preincubatio n of the membranes with the OPs increased this site's affinity for Car b, In absence of agonist, 100 mu M of the OPs increased the binding of [H-3]TCP by two-to fivefold with the following order of decreasing po tency: PS > CPO > CPS > PO, The data suggest that in addition to inhib ition of acetylcholinesterase, these OPs bind to a site on the nAChR t hat is different from the sites that bind ACh or TCP and that this bin ding induces nAChR desensitization. The relevance of this direct actio n of OPs on nAChRs on their acute toxicities is discussed. (C) 1997 Ac ademic Press.