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Published online before print September 12, 2008

0031-6997/08/6003-243-260$7.00
Pharmacol Rev 60:243-260, 2008

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IUPHAR Nomenclature Report

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

Richard W. Olsen and 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.)

Abstract
I. Introduction: Definition of GABAA Receptors
    A. Ionotropic GABA-Gated Anion Channels
    B. The Cys-Loop Pentameric Ligand-Gated Ion Channel Superfamily
    C. The GABAA Receptor Family of 19 Genes
    D. The rho Subunits and the GABAC Receptor Concept: Not Recommended
II. Structural Basis of Receptor Classification
    A. GABAA Receptor Family and Superfamily (Homology of Structure and Function)
        1. Subunit Gene List.
        2. Subunit Splice Variants.
    B. Heteropentameric Assembly Produces Complex Subtype Heterogeneity
    C. Criteria for Inclusion on a List of Native Receptor Subtypes
        1. Subtypes Based on Structure, Pharmacology, and Function: Nomenclature Guidelines.
        2. Discussion of the Criteria.
III. Working List of Native GABAA Receptor Subtypes
    A. Evidence for Subtypes from Localization, Abundance, Subunit Composition, and Stoichiometry Data
    B. Pharmacological Evidence for Subtypes
        1. Benzodiazepine Site Ligands Distinguish between Subtypes Based on alpha and gamma Subunits.
        2. Evidence from Other Ligands (GABA, Picrotoxin, General Anesthetics, and Ethanol) Confirms and Extends the List of Receptors.
    C. Other, Nonligand, Delineation of Heterogeneity
        1. Subunit Composition.
            a. Minor subunits (rho1–3, gamma1, gamma3, epsilon, theta, and pi).
            b. alpha/β Pentamers.
            c. Multiple alpha or β (other?) isoforms per pentamer.
            d. Receptors containing 1, 2, 4, or 5 different subunits.
        2. Localization, Trafficking, Post-Translational Modifications, and Associated Proteins.
    D. Tentative List of Naturally Occurring Receptor Subtypes
IV. Concluding Remarks
In this review we attempt to summarize experimental evidence on the existence of defined native GABAA receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge. This will serve to update the most recent classification of GABAA receptors (Pharmacol Rev 50:291–313, 1998) approved by the Nomenclature Committee of the International Union of Pharmacology. GABAA receptors are chloride channels that mediate the major form of fast inhibitory neurotransmission in the central nervous system. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share struc-tural and functional homology with other members of that family. GABAA receptors are assembled from a family of 19 homologous subunit gene products and form numerous, mostly hetero-oligomeric, pentamers. Such receptor subtypes with properties that depend on subunit composition vary in topography and ontogeny, in cellular and subcellular localization, in their role in brain circuits and behaviors, in their mechanisms of regulation, and in their pharmacology. We propose several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a list of native hetero-oligomeric subtypes. With these criteria, we develop a working GABAA receptor list, which currently includes 26 members, but will undoubtedly be modified and grow as information expands. The list is divided into three categories of native receptor subtypes: "identified," "existence with high probability," and "tentative."

Address correspondence to: Dr. Richard W. Olsen, Department of Molecular and Medical Pharmacology, Geffen School of Medicine at UCLA, Room CHS 23-120, 650 Young Drive South, Los Angeles, CA 90095-1735. E-mail: rolsen{at}mednet.ucla.edu




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