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 examined by whole-cell voltage-clamp technique. 2. A concentration-response curve for the specific nicotinic agonist dimethylphenylpiperazinium iodide (DMPP) was first determined. This agonist produced increasing whole-cell currents up to a concentration of 100 microM (EC50 = 13 microM), then decreased responses at higher concentrations. 3. The barbiturates (amobarbital, secobarbital, pentobarbital) and procaine produced reversible inhibition of DMPP-induced currents at clinically used concentrations. The two classes of drugs differed in the voltage dependence of the inhibition: procaine-induced inhibition was increased at more negative transmembrane holding potentials (-90 vs. -45 mV); whereas amobarbital-induced inhibition did not vary at different transmembrane potentials. 4. Mutant forms of the nAChR, containing single amino acid changes in the M2 regions of alpha and beta subunits, showed increased sensitivity to procaine but no change in sensitivity to amobarbital-induced inhibition. 5. These electrophysiologic studies provide further evidence that barbiturates and local anesthetics produce inhibition of the nAChR at different sites.
Department of Anesthesia, University of California, San Francisco 94143.
C S
CS
Yost
B A
BA
Dodson
D000495:Allosteric Site; D000595:Amino Acid Sequence; D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology*; D001665:Binding Sites; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D018733:Nicotinic Antagonists; D009865:Oocytes; D010424:Pentobarbital / Q000494:pharmacology; D011343:Procaine / Q000494:pharmacology*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D012631:Secobarbital / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects*; D014982:Xenopus laevis
D001463:Barbiturates; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D015222:Sodium Channels; D012631:Secobarbital; D011343:Procaine; D004246:Dimethylphenylpiperazinium Iodide; D000654:Amobarbital; D010424:Pentobarbital