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 channels and like most such channels, ethanol and longer chain alcohols modulate their activity. In the present studies, the effects of alcohols were characterized on defined combinations of human neuronal nAChR subunits heterologously expressed in Xenopus oocytes. Short-chain alcohols, such as ethanol, propanol, and butanol potentiated ACh-induced currents in both alpha(2)beta(4) and alpha(4)beta(4) nAChRs. Longer chain alcohols, however, inhibited these receptor subtypes. Small increases in alcohol chain length were sufficient to produce a "crossover" from potentiation to inhibition. For the alpha(2)beta(4) receptor subunit combination, butanol clearly potentiated while pentanol inhibited ACh-induced current, whereas for alpha(4)beta(4) nAChR, propanol potentiated, butanol had no discernable effect, and pentanol inhibited receptor function. Fluorinated analogs of ethanol, propanol, 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 results support the hypothesis that for both alpha(2)beta(4) and alpha(4)beta(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 suggested that the inhibitory and facilitatory effects of alcohols are mediated 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 properties of the molecule.
Godden
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Department of Pharmacology and Neuroscience Program, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Harris
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RA
Dunwiddie
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D000438:Alcohols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D006801:Humans; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D000438:Alcohols; D012333:RNA, Messenger; D011978:Receptors, Nicotinic