Cited by 144Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyReceptor Mechanisms and Signaling

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GABAA receptor subtypes: the ‘one glass of wine’ receptors

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Olsen, Richard W., Hanchar, Harry J., Meera, Pratap, Wallner, Martin·2007·Alcohol

DOI 10.1016/j.alcohol.2007.04.006PMC PMC2852584

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Abstract

This review discusses evidence for and apparent controversy about, gamma-aminobutyric acid type A (GABAA) receptor (GABAAR) subtypes that mediate alcohol effects experienced during social drinking. GABAARs that contain the beta3 and delta subunits were shown to be enhanced by alcohol concentrations that mirror the concentration dependence of alcohol responses in humans. A mutation (alpha6R100Q) previously found in alcohol nontolerant rats in the cerebellar GABAAR alpha6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (alpha6-100QQ) and further increases alcohol sensitivity of tonic GABA currents (mediated by alpha6betadelta receptors) in cerebellar granule cells of alpha6-100QQ rats and in recombinant alpha6R100Qbeta3delta receptors. This provided the first direct evidence that these types of receptors mediate behavioral effects of ethanol. Furthermore, the behavioral alcohol antagonist Ro15-4513 specifically reverses ethanol enhancement on alpha4/6beta3delta receptors. Unexpectedly, native and recombinant alpha4/6beta3delta receptors bind the behavioral alcohol antagonist Ro15-4513 with high affinity and this binding is competitive with EtOH, suggesting a specific and mutually exclusive (competitive) ethanol/Ro15-4513 site, which explains the puzzling activity of Ro15-4513 as a behavioral alcohol antagonist. Our conclusion from these findings is that alcohol/Ro15-4513-sensitive GABAAR subtypes are important alcohol targets and that alcohol at relevant concentrations is more specific than previously thought. In this review, we discuss technical difficulties in expressing recombinant delta subunit-containing receptors in oocytes and mammalian cells that may have contributed to negative results and confusion. Not only because we have reproduced detailed positive results numerous times, and we and many others have built extensively on basic findings, but also because we explain and combine many previously puzzling results into a coherent and highly plausible paradigm on how alcohol exerts an important part of its action in the brain, we are confident about our findings and conclusions. However, many important open questions remain to be answered.

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Authors: Olsen, R. W., Hanchar, H. J., Meera, P., & Wallner, M.
Affiliations: University of California, Los Angeles (US)
Corresponding author: Wallner, Martin
ORCID: Meera, Pratap
Wallner, Martin
Venue: Alcohol
Publisher: Elsevier BV
Published: 2007-05
Volume: 41
Issue: 3
Pages: 201-209
ISSN: 0741-8329 (ISSN-L)
DOI: 10.1016/j.alcohol.2007.04.006
PMC: PMC2852584
OpenAlex: W1978493649
Cited by: 142
References: 125
Citations by year: 2024: 4 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 2 · 2019: 9 · 2018: 11 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 16 · 2013: 6 · 2012: 15
FWCI: 0.96
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Alcohol (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism (F31AA015460, AA 015460, AA07680, R37AA007680, R01AA007680)
National Institute of Neurological Disorders and Stroke (NS-35985, P01NS035985)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: GABAA receptor subtypes, alcohol effects, social drinking, alpha6 subunit, cerebellar granule cells, Ro 15-4513, alcohol sensitivity
MeSH terms: Ethanol, Animals, Azides, Benzodiazepines, Central Nervous System Depressants, Humans, Receptors, GABA-A, Wine

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GABAA receptor subtypes: the ‘one glass of wine’ receptors

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