TY - JOUR
T1 - Dual action of n-butanol on neuronal nicotinic α4β2 acetylcholine receptors
AU - Zuo, Yi
AU - Yeh, Jay Z.
AU - Narahashi, Toshio
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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 α4β2 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 EC50 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-β-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 μM), while inhibiting the currents induced by high concentrations of ACh (100-3000 μM). In addition, butanol at a low concentration (10 mM) suppressed the currents evoked by 10 to 3000 μM 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.
AB - 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 α4β2 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 EC50 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-β-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 μM), while inhibiting the currents induced by high concentrations of ACh (100-3000 μM). In addition, butanol at a low concentration (10 mM) suppressed the currents evoked by 10 to 3000 μM 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.
UR - http://www.scopus.com/inward/record.url?scp=0037371413&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037371413&partnerID=8YFLogxK
U2 - 10.1124/jpet.102.044537
DO - 10.1124/jpet.102.044537
M3 - Article
C2 - 12604691
AN - SCOPUS:0037371413
VL - 304
SP - 1143
EP - 1152
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -