Role of the GABA(A)β2, GABA(A)α6, GABA(A)α1 and GABA(A)γ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence

El Wui Loh, David Ball

Research output: Contribution to journalReview article

51 Citations (Scopus)

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the γ2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (β2, α6, α1 and γ2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)α6 and GABA(A)γ2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)γ2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)413-423
Number of pages11
JournalNeurochemistry International
Volume37
Issue number5-6
DOIs
Publication statusPublished - Nov 1 2000
Externally publishedYes

Fingerprint

GABA-A Receptors
Multigene Family
gamma-Aminobutyric Acid
Alcoholism
Pharmaceutical Preparations
Alcohols
Gene Knockout Techniques
Genes
Medical Genetics
Genetic Association Studies
Benzodiazepines
GABA-B Receptors
Aminobutyrates
Phenotype
Amino Acids
Chromosomes, Human, Pair 11
Human Chromosomes
Ethnic Groups
Knockout Mice
Serine

Keywords

  • Alcohol
  • Benzodiazepines
  • Chromosome 5q33-34
  • GABA(A)
  • Genetic polymorphisms
  • Receptor subunit

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

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title = "Role of the GABA(A)β2, GABA(A)α6, GABA(A)α1 and GABA(A)γ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence",
abstract = "γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the γ2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (β2, α6, α1 and γ2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)α6 and GABA(A)γ2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)γ2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.",
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T1 - Role of the GABA(A)β2, GABA(A)α6, GABA(A)α1 and GABA(A)γ2 receptor subunit genes cluster in drug responses and the development of alcohol dependence

AU - Loh, El Wui

AU - Ball, David

PY - 2000/11/1

Y1 - 2000/11/1

N2 - γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the γ2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (β2, α6, α1 and γ2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)α6 and GABA(A)γ2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)γ2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.

AB - γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system and it acts at the GABA(A) and GABA(B) receptors. A possible role for the GABA(A) receptors in alcohol action has been derived from in vitro cell models, animal studies and human research. GABA(A) subunit mRNA expression in cell models has suggested that the long form of the γ2 subunit is essential for ethanol enhanced potentiation of GABA(A) receptors, by phosphorylation of a serine contained within the extra eight amino acids. Several animal studies have demonstrated that alterations in drug and alcohol responses may be caused by amino-acid differences at the GABA(A)α6 and GABA(A)γ2 subunits. An Arg100/Glu100 change at the GABA(A)α6 subunit conferring altered binding efficacy of the benzodiazepine inverse agonist Ro 15-4513, was found between the AT (alcohol tolerance) and ANT (alcohol non-tolerance) rats. Several loci related to alcohol withdrawal on mouse chromosome 11 which corresponds to the region containing four GABA(A) subunit (β2, α6, α1 and γ2) genes on human chromosome 5q33-34, were also identified. Gene knockout studies of the role of GABA(A)α6 and GABA(A)γ2 subunit genes in mice have demonstrated an essential role in the modulation of other GABA(A) subunit expression and the efficacy of benzodiazepine binding. Absence of the GABA(A)γ2 subunit gene has more severe effects with many of the mice dying shortly after birth. Disappointingly few studies have examined the effects of response to alcohol in these gene knockout mice. Human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have a role in the development of alcohol dependence, although their contributions may vary between ethnic group and phenotype. In summary, in vitro cell, animal and human genetic association studies have suggested that the GABA(A)β2, α6, α1 and γ2 subunit genes have an important role in alcohol related phenotypes (300 words). Copyright (C) 2000 Elsevier Science Ltd.

KW - Alcohol

KW - Benzodiazepines

KW - Chromosome 5q33-34

KW - GABA(A)

KW - Genetic polymorphisms

KW - Receptor subunit

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U2 - 10.1016/S0197-0186(00)00054-1

DO - 10.1016/S0197-0186(00)00054-1

M3 - Review article

C2 - 10871693

AN - SCOPUS:0034310739

VL - 37

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EP - 423

JO - Neurochemistry International

JF - Neurochemistry International

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