Dual action of n-butanol on neuronal nicotinic alpha4beta2 acetylcholine receptors.
N-alcohols exert a dual action on neuronal nicotinic acetylcholine (ACh) receptors with short-chain alcohols exhibiting potentiating action and long-chain alcohols exhibiting inhibitory action. n-Butanol lies at the transition point from potentiation to inhibition. To elucidate the mechanism of dual action of alcohols, the effects of n-butanol on the human alpha4beta2 ACh receptors expressed in the HEK293 cell line were analyzed in detail by the whole-cell patch-clamp technique. Prolonged applications of n-butanol evoked small currents with an EC(50) value of 230 +/- 90 mM and a Hill coefficient of 1.8 +/- 0.4. This current was blocked by either the ACh channel blocker mecamylamine or the receptor blocker dihydro-beta-erythroidine, indicating that butanol activated receptors as a partial agonist. As expected from its partial agonist action, n-butanol also modulated ACh-induced currents in a concentration-dependent manner. Butanol at 300 mM potentiated currents induced by low concentrations of ACh (</=30 microM), while inhibiting the currents induced by high concentrations of ACh (100-3,000 microM). In addition, butanol at a low concentration (10 mM) suppressed the currents evoked by 10 to 3,000 microM ACh, a result consistent with a channel-blocking action. Most features of n-butanol effects were satisfactorily simulated by a model in which butanol acts as a partial agonist and as a channel blocker.
Zuo
Yi
Y
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.
Yeh
Jay Z
JZ
Narahashi
Toshio
T
D020001:1-Butanol / Q000494:pharmacology*; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*
D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D020001:1-Butanol