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OtherIUPHAR Nomenclature Report

International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update

Richard W. Olsen and Werner Sieghart
Pharmacological Reviews September 2008, 60 (3) 243-260; DOI: https://doi.org/10.1124/pr.108.00505
Richard W. Olsen
Department of Molecular and Medical Pharmacology, Geffen School of Medicine at UCLA, Los Angeles, California (R.W.O.); and Division of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria (W.S.)
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Werner Sieghart
Department of Molecular and Medical Pharmacology, Geffen School of Medicine at UCLA, Los Angeles, California (R.W.O.); and Division of Biochemistry and Molecular Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria (W.S.)
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  • Fig. 1.
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    Fig. 1.

    Schematic rendition of a Cys-loop pentameric ligand-gated ion channel receptor. The different shades of gray signify different subunits (unspecified here), assembled in different permutations to generate multiple hetero-oligomers. The purpose of this review is to attempt to list the naturally occurring subtypes of GABAA receptors. Similar chores face those interested in other members of the superfamily as well as other structural types of LGIC. [Adapted from Haefely W (1987) Structure and function of the benzodiazepine receptor. Chimia 41:389–396. Copyright © 1987 Swiss Chemical Society. Used with permission.]

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    Fig. 2.

    Dendrogram of the known 19 genes for human GABAA receptors. The distances along each line are proportional to the degree of sequence identity between the different homologous subunits. The Greek letters signify subunit families of high (>70%) identity, with different Greek letter subunit families showing homology but lower sequence identity. The distances reflect the evolutionary times required to generate sufficient sequence divergence. [Reproduced from Simon J, Wakimoto H, Fujita N, Lalande M, and Barnard EA (2004) Analysis of the set of GABAA receptor genes in the human genome. J Biol Chem 279:41422–41435. Copyright © 2004. Used with permission.]

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    TABLE 1

    GABAA receptor subunit gene list Chromosome data from Simon et al. (2004).

    Subunit Gene Chromosome
    Human Mouse Rat
    α1 GABRA1 5q34 11 10
    α2 GABRA2 4p12 5 14
    α3 GABRA3 Xq28 X X
    α4 GABRA4 4p12 5 14
    α5 GABRA5 15q13.2 7 1
    α6 GABRA6 5q34 11 10
    β1 GABRB1 4p12 5 14
    β2 GABRB2 5q34 11 10
    β3 GABRB3 15q13.2 7 1
    γ1 GABRG1 4p12 5 14
    γ2 GABRG2 5q34 11 10
    γ3 GABRG3 15q13.2 7 1
    δ GARBD 1p36.3 4 5
    ϵ GABRE Xq28 X X
    θ GABRQ Xq28 X X
    π GABRP 5q35.1 11 10
    ρ1 GABRR1 6q15 4 5
    ρ2 GABRR2 6q15 4 5
    ρ3 GABRR3 3q12.1 16 11
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    TABLE 2

    Criteria for inclusion on a list of native receptor subtypes

    I. Recombinant receptors
       A. Evidence for their formation, subunit composition, and stoichiometry, using recombinant receptor expression in heterologous cell systems
          1. The subunit polypeptides must be shown to be expressed
          2. The subunit polypeptides must be shown to coassemble
             a. Coimmunoprecipitation
             b. Physical demonstration of subunit interactions by FRET or similar technique
             c. Formation of pentamers
             d. Unique subunit arrangement, e.g., using concatemers
          3. The corresponding recombinant receptor subtype must be functional
       B. Evidence for unique properties, including pharmacology
          1. Unique biophysical characteristics
          2. Unique pharmacology
             a. Receptor subtype-selective agonists, antagonists, allosteric modulators
             b. Receptor subtype-selective radioligands
             c. Potency and efficacy for a series of ligands
             d. Macrokinetic measures (e.g., apparent EC50 values and binding constants for a series of ligands)
    II. Native receptors
       A. Colocalization of subunits
          1. Tissue colocalization
          2. Cell colocalization (in situ, single-cell RT-PCR)
          3. Subcellular colocalization (light and electron microscopy)
       B. Physical demonstration of subunit interactions (e.g., by coimmunoprecipitation)
       C. Functional demonstration:
          1. Evidence that a given receptor is expressed in real neurons by showing properties (assessed with electrophysiology) corresponding with a recombinant receptor candidate; microscopy may complement
          2. Evidence that a given subunit or subunit combination participates in a specific function in vitro or in vivo using genetically modified mice
    • View popup
    TABLE 3

    GABAA receptor native oligomer list

    Category A: Identified
       α1β2γ2
       α2βγ2
       α3βγ2
       α4βγ2
       α4β2δ
       α4β3δ
       α5βγ2
       α6βγ2
       α6β2δ
       α6β3δ
       ρ
    Category B: Existence with high probability
       α1β3γ2
       α1βδ
       α5β3γ2
       αβ1γ/αβ1δ
       αβ
       α1α6βγ/α1α6βδ
    Category C: Tentative
       ρ1
       ρ2
       ρ3
       αβγ1
       αβγ3
       αβθ
       αβϵ
       αβπ
       αxαyβγ2
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Pharmacological Reviews: 60 (3)
Pharmacological Reviews
Vol. 60, Issue 3
1 Sep 2008
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OtherIUPHAR Nomenclature Report

International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update

Richard W. Olsen and Werner Sieghart
Pharmacological Reviews September 1, 2008, 60 (3) 243-260; DOI: https://doi.org/10.1124/pr.108.00505

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OtherIUPHAR Nomenclature Report

International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update

Richard W. Olsen and Werner Sieghart
Pharmacological Reviews September 1, 2008, 60 (3) 243-260; DOI: https://doi.org/10.1124/pr.108.00505
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  • Article
    • Abstract
    • I. Introduction: Definition of GABAA Receptors
    • II. Structural Basis of Receptor Classification
    • III. Working List of Native GABAA Receptor Subtypes
    • IV. Concluding Remarks
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