Correlation between molecular volume and effects of n-alcohols on human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes

Nicotinic acetylcholine receptors (nAChRs) are neurotransmitter-gated ion c hannels and like most such channels, ethanol and longer chain alcohols modu late their activity. In the present studies, the effects of alcohols were c haracterized on defined combinations of human neuronal nAChR subunits heter ologously expressed in Xenopus oocytes. Short-chain alcohols, such as ethan ol, propanol, and butanol potentiated ACh-induced currents in both alpha (2 )beta (4) and alpha (4)beta (4) nAChRs. Longer chain alcohols, however, inh ibited these receptor subtypes. Small increases in alcohol chain length wer e sufficient to produce a "crossover" from potentiation to inhibition. For the alpha (2)beta (4) receptor subunit combination, butanol clearly potenti ated while pentanol inhibited ACh-induced current, whereas for alpha (4)bet a (4) nAChR, propanol potentiated, butanol had no discernable effect, and p entanol inhibited receptor function. Fluorinated analogs of ethanol, propan ol, and butanol were used to determine whether the effects of the alcohols were dependent upon chain length or whether another related attribute, such as molecular volume, was the defining characteristic. The experimental res ults support the hypothesis that for both alpha (2)beta (4) and alpha (4)be ta (4) receptor subtypes, molecular volume appears to be the most important determinant of both the potency as well as the direction of modulation of nAChR function by n-alcohols and related compounds. Although it has been su ggested that the inhibitory and facilitatory effects of alcohols are mediat ed by actions at different sites on the receptor molecule, the present data suggest the possibility that there may be a single site of alcohol action and that the nature of this action is dependent upon the physical propertie s of the molecule.