Abstract
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.
Footnotes
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This work was supported by National Institutes of Health Grant AA07836.
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DOI: 10.1124/jpet.102.044537
- Abbreviations:
- nAChR
- nicotinic acetylcholine receptor
- EPC
- end-plated current
- ACh
- acetylcholine
- nnAChR
- neuronal nAChR
- HEK
- human embryonic kidney
- DHβE
- dihydro-β-erythroidine
- Received September 18, 2002.
- Accepted November 26, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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