INHIBITION OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR BY BARBITURATES AND BY PROCAINE - DO THEY ACT AT DIFFERENT SITES

1. The effects of three barbiturates and the local anesthetic procaine on the ion channel function of mouse nicotinic acetylcholine receptor (nAChR) muscle subtype expressed in Xenopus laevis oocytes were exami ned by whole-cell voltage-clamp technique. 2. A concentration-response curve for the specific nicotinic agonist dimethylphenylpiperazinium i odide (DMPP) was first determined. This agonist produced increasing wh ole-cell currents up to a concentration of 100 muM (EC50 = 13 muM), th en decreased responses at higher concentrations. 3. The barbiturates ( amobarbital, secobarbital, pentobarbital) and procaine produced revers ible inhibition of DMPP-induced currents at clinically used concentrat ions. The two classes of drugs differed in the voltage dependence of t he inhibition: procaine-induced inhibition was increased at more negat ive transmembrane holding potentials (-90 vs. -45 mV); whereas amobarb ital-induced inhibition did not vary at different transmembrane potent ials. 4. Mutant forms of the nAChR, containing single amino acid chang es in the M2 regions of alpha and beta subunits, showed increased sens itivity to procaine but no change in sensitivity to amobarbital-induce d inhibition. 5. These electrophysiologic studies provide further evid ence that barbiturates and local anesthetics produce inhibition of the nAChR at different sites.