Abstract
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 inXenopus oocytes. Short-chain alcohols, such as ethanol, propanol, and butanol potentiated ACh-induced currents in both α2β4 and α4β4nAChRs. 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 α2β4 receptor subunit combination, butanol clearly potentiated while pentanol inhibited ACh-induced current, whereas for α4β4 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 α2β4 and α4β4receptor 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.
Footnotes
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Send reprint requests to: Thomas V. Dunwiddie, Ph.D., Department of Pharmacology, Box C236, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Denver, CO 80262. E-mail:Tom.Dunwiddie{at}UCHSC.edu
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This study was supported by National Institutes of Health Grants AA03527 (to T.V.D.), AA06399 (to R.A.H.), and AA03527 (to R.A.H.). This work was presented in preliminary form at the Society for Neuroscience meeting in Miami Beach, FL, October, 1999.
- Abbreviations:
- nAChR
- neuronal nicotinic acetylcholine receptor
- GABA
- γ-aminobutyric acid
- DMSO
- dimethyl sulfoxide
- ACh
- acetylcholine
- NMDA
- N-methyl-d-aspartate
- HT
- hydroxytryptamine
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- R
- receptor
- KA
- kainic acid
- Received September 18, 2000.
- Accepted December 1, 2000.
- U.S. Government
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