The R100Q mutation of the GABAA α6 receptor subunit may contribute to voluntary aversion to ethanol in the sNP rat line

Saba, Luisella; Porcella, Anna; Congeddu, Elena; Colombo, Giancarlo; Peis, Michela; Pistis, Marco; Gessa, Gian Luigi; Pani, Luca

doi:10.1016/s0169-328x(01)00003-1

Cited by 37 publications

(23 citation statements)

References 31 publications

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“…The same α6(R100Q) polymorphism has also been found enriched in the independently derived "Sardinian alcohol non-preferring sNP" rats (Saba et al, 2001;Sanna et al, 2003), a rat line that was segregated from Sardinian alcohol preferring rats (sP) based on their voluntary alcohol consumption. The identification of the same "mutation" occurring in 2 different rat lines is likely due to the selection of a fairly frequent naturally occurring α6(100Q) allele.…”

Section: A Polymorphism In the Cerebellar Gaba A R α6(α6r100q) Subunimentioning

confidence: 76%

“…In contrast, the α6-100Q allele is only enriched in the alcohol non-preferring animals (Saba et al, 2001), indicating that the α6-100Q allele might contribute to the alcohol non-preference, but its relative importance is lower when compared to other genes, yet to be identified, which contribute to alcohol preference in these animals.…”

Section: A Polymorphism In the Cerebellar Gaba A R α6(α6r100q) Subunimentioning

confidence: 93%

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Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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GABA A receptors (GABA A Rs) are the main inhibitory neurotransmitter receptors and have long been implicated in mediating at least part of the acute actions of ethanol. For example, ethanol and GABAergic drugs including barbiturates and benzodiazepines share many pharmacological properties. Besides the prototypical synaptic GABA A R subtypes, nonsynaptic GABA A Rs have recently emerged as important regulators of neuronal excitability. While high doses (≥100 mM) of ethanol have been reported to enhance activity of most GABA A R subtypes, most abundant synaptic GABA A Rs are essentially insensitive to ethanol concentrations that occur during social ethanol consumption (<30 mM). However, extrasynaptic δ and β3 subunit-containing GABA A Rs, associated in the brain with α4or α6 subunits, are sensitive to low millimolar ethanol concentrations, as produced by drinking half a glass of wine. Additionally, we found that a mutation in the cerebellar α6 subunit (α6R100Q), initially reported in rats selectively bred for increased alcohol sensitivity, is sufficient to produce increased alcohol-induced motor impairment and further increases of alcohol sensitivity in recombinant α6β3δ receptors. Furthermore, the behavioral alcohol antagonist Ro15-4513 blocks the low dose alcohol enhancement on α4/6/β3δ receptors, without reducing GABA-induced currents. In binding assays α4β3δ GABA A Rs bind [ 3 H] Ro15-4513 with high affinity, and this binding is inhibited, in an apparently competitive fashion, by low ethanol concentrations, as well as analogs of Ro15-4513 that are active to antagonize ethanol or Ro15-4513's block of ethanol. We conclude that most low to moderate dose alcohol effects are mediated by alcohol actions on alcohol/Ro15-4513 binding sites on GABA A R subtypes.

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Section: A Polymorphism In the Cerebellar Gaba A R α6(α6r100q) Subunimentioning

confidence: 76%

Section: A Polymorphism In the Cerebellar Gaba A R α6(α6r100q) Subunimentioning

confidence: 93%

Low dose acute alcohol effects on GABAA receptor subtypes

Wallner

Hanchar

Olsen

2006

Pharmacology & Therapeutics

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“…In two such lines, the ANT and the Sardinian nonpreferring rats, the Gabra6 100R and Gabra6 100Q alleles have been found to segregate into ethanol-hyposensitive and -hypersensitive groups, respectively. For the Sardinian nonpreferring rats, it is a partial segregation 25 , whereas for the alcohol tolerant (AT)/alcohol non-tolerant (ANT) line, almost all of the ANT rats are homozygous for the Gabra6 100Q allele 24 . However, because the α6-R100Q polymorphism had not been shown to affect ethanol sensitivity of recombinant receptors 24 and because backcrosses of ANT/AT rats had led researchers to question the correlation between this polymorphism and the ethanol-hypersensitive phenotype, it has been concluded that genetic differences other than the one causing the α6-R100Q polymorphism were important 27,38 .…”

Section: Gabra6 100q Allele and Behavioral Sensitivity To Ethanolmentioning

confidence: 99%

“…To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymorphism in the gene encoding rat α6 (Gabra6). This polymorphism is of interest because it has been reported to be present in alcohol-nontolerant (ANT) rats 24 and enriched in Sardinian alcohol-nonpreferring rats 25 , two lines of animals selectively bred either for heightened ethanol-induced motor impairment (ANT rats) or for aversion to ethanol (Sardinian nonpreferring rats). A single nucleotide change (from a guanine to an adenine) leads to a single amino acid substitution, from arginine (R) to glutamine (Q), at amino acid position 100 in α6.…”

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confidence: 99%

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

et al. 2005

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Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABA A receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6 100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.Humans have been consuming alcohol for thousands of years, and the use of alcoholic beverages pervades human culture and society and can have substantial health effects 1 . Different mechanisms by which ethanol might depress brain function have been proposed based on ethanol's ability to modulate a wide variety of ion channels 2-4 , neurotransmitter receptors 5-10 and transporters 11 . Among these diverse targets, however, GABARs are arguably the most attractive candidates. This is in part because other classes of known GABAR modulators such as benzodiazepines, barbiturates and certain anesthetics lead to behavioral effects that closely resemble ethanol intoxication. Yet despite strong evidence implicating GABARs in ethanol's action, critical details remain unclear. For instance, although it is known that native GABARs are heteropentamers assembled from 19 possible subunits 12,13 , it has not been possible to link the activity of particular GABAR subunits to changes in behavioral sensitivity to ethanol.Recent studies suggest that specific combinations of GABAR subunits (those containing α4β3δ and α6β3δ) are uniquely sensitive to ethanol, showing dose dependencies that mirror blood alcohol levels associated with intoxication in humans 9,10 . GABARs containing α4 and δ subunits are expressed in many brain regions 14,15 , but α6 is found in only two types of neurons (cerebellar granule cells and granule cells in the cochlear nucleus) and is expressed together with δ only in cerebellar granule cells 14,16,17 . In granule cells α6 and δ combine with β subunits Correspondence should be addressed to M.W. (mwallner@mednet.ucla.edu) or T.S.O. (otist@ucla.edu). 3 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We set out to examine whether such extrasynaptic GABARs containing α6 and δ subunits account for behavioral effects of ethanol at moderately intoxicating doses. To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymo...

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“…Furthermore the surprising finding that Ro15-4513 is a competitive alcohol antagonist on α4β3δ receptors now also provides a plausible explanation for the previously puzzling finding that Ro15-4513 can antagonize most behavioral alcohol actions at pharmacologically relevant doses. Our observation that the α6R100Q mutation is a frequently occurring allele in laboratory rats and leads to a further increase in EtOH potency on α6β3δ receptors (in vivo and in vitro) finally provides a plausible explanation for why the α6R100Q polymorphism has been segregated during selective breeding for alcohol-supersensitive phenotypes in three independent studies (Uusi-Oukari and Korpi, 1991;Saba et al, 2001;Carr et al, 2003).…”

Section: Summary Open Questions and Future Developments And Apparentmentioning

confidence: 70%

GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

128

121

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This review discusses evidence for and apparent controversy about, GABA A receptor subtypes that mediate alcohol effects experienced during social drinking. GABA A receptors that contain the β3 and δ subunits were shown to be enhanced by alcohol concentrations that mirror the concentrationdependence of alcohol responses in humans. A mutation (α6R100Q) previously found in alcohol non-tolerant (ANT) rats in the cerebellar GABA A receptor α6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (α6-100QQ) and further increases alcohol-sensitivity of tonic GABA currents (mediated by α6βδ receptors) in cerebellar granule cells of α6-100QQ rats and in recombinant α6R100Qβ3δ 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 α4/6β3δ receptors. Unexpectedly, native and recombinant α4/6β3δ 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 GABA A receptor 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 δ 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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The R100Q mutation of the GABAA α6 receptor subunit may contribute to voluntary aversion to ethanol in the sNP rat line

Cited by 37 publications

References 31 publications

Low dose acute alcohol effects on GABAA receptor subtypes

Low dose acute alcohol effects on GABAA receptor subtypes

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

GABAA receptor subtypes: the “one glass of wine” receptors

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