GABAB Receptors: Physiological Functions and Mechanisms of Diversity

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Abstract

GABAB receptors are the G-protein-coupled receptors (GPCRs) for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system. GABAB receptors are implicated in the etiology of a variety of psychiatric disorders and are considered attractive drug targets. With the cloning of GABAB receptor subunits 13 years ago, substantial progress was made in the understanding of the molecular structure, physiology, and pharmacology of these receptors. However, it remained puzzling that native studies demonstrated a heterogeneity of GABAB responses that contrasted with a very limited diversity of cloned GABAB receptor subunits. Until recently, the only firmly established molecular diversity consisted of two GABAB1 subunit isoforms, GABAB1a and GABAB1b, which assemble with GABAB2 subunits to generate heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors. Using genetic, ultrastructural, biochemical, and electrophysiological approaches, it has been possible to identify functional properties that segregate with these two receptors. Moreover, receptor modifications and factors that can alter the receptor response have been identified. Most importantly, recent data reveal the existence of a family of auxiliary GABAB receptor subunits that assemble as tetramers with the C-terminal domain of GABAB2 subunits and drastically alter pharmacology and kinetics of the receptor response. The data are most consistent with native GABAB receptors minimally forming dimeric assemblies of units composed of GABAB1, GABAB2, and a tetramer of auxiliary subunits. This represents a substantial departure from current structural concepts for GPCRs.

Introduction

GABA is the main inhibitory transmitter in the vertebrate central nervous system. GABAergic neurotransmission relies on two classes of receptors. Ionotropic GABAA receptors mediate fast GABA responses by triggering chloride channel openings. Metabotropic GABAB receptors are members of the family 3 (or family C) G-protein-coupled receptors (GPCRs) and mediate slower GABA responses by activating G-proteins and influencing second messenger systems (Bettler and Tiao, 2006, Bowery, 2006, Couve et al., 2000, Kornau, 2006, Ulrich and Bettler, 2007). These two classes of receptors were originally discriminated based on pharmacological differences (Bowery et al., 1980, Hill and Bowery, 1981). It was observed that the evoked release of adrenaline, dopamine, and serotonin was decreased by GABA acting on a receptor different from the known GABAA receptors. This decrease of evoked neurotransmitter release was surprisingly independent of the GABAA antagonist bicuculline but sensitive to baclofen. The terms GABAA and GABAB were introduced to distinguish bicuculline- from baclofen-sensitive receptors (Hill & Bowery, 1981). Since then, kinetic and pharmacological differences between native GABAB responses further suggested the existence of molecularly distinct GABAB receptor subtypes. However, cloning of GABAB receptors revealed an unexpectedly low structural diversity, unlike what is observed with the sequence-related metabotropic glutamate receptors (mGluRs). Only two heteromeric GABAB receptors consisting of GABAB1a or GABAB1b subunits in combination with GABAB2 subunits were identified. It was therefore important to address how such a limited structural diversity leads to a variety of pharmacologically and kinetically distinct native GABAB responses. Here, we review evidence for heterogeneous native GABAB responses and discuss mechanisms that generate functional and pharmacological diversity in the GABAB receptor system.

Section snippets

Physiological Functions of GABAB Receptors

GABAB receptors influence their effectors via the Gα and Gβγ subunits of the activated G protein. The first GABAB effector characterized was adenylate cyclase whose activity was shown to be inhibited via the Gαi/Gαo subunits (Xu & Wojcik, 1986). Unfortunately, the physiological consequences of this modulation are poorly understood but include effects on transcription factors, kinases and intracellular Ca2+ signaling (Couve et al., 2002, New et al., 2006, Ren and Mody, 2003, Steiger et al., 2004

Heterogeneity of Native GABAB Responses

As highlighted in the previous section, GABAB receptors are involved in a variety of neuronal functions. During the past 20 years, heterogeneous native GABAB responses suggested the existence of multiple receptor subtypes (Bonanno and Raiteri, 1993b, Raiteri, 2006, Raiteri, 2008). Below, we review some of the pharmacological and functional evidence for differences between (A) pre- and postsynaptic GABAB receptors, (B) presynaptic GABAB auto- and heteroreceptors, and (C) postsynaptic GABAB

Functions of the Cloned GABAB Receptor Subtypes

Given the heterogeneity observed with native GABAB responses, many researchers in the field expected the existence of multiple GABAB receptor subtypes. However, cloning efforts only produced two molecular subtypes of GABAB receptors (Marshall et al., 1999). Molecular diversity in the GABAB system is based on the subunit isoforms GABAB1a and GABAB1b, both of which combine with GABAB2 to form heteromeric GABAB(1a,2) and GABAB(1b,2) receptors. Recombinant experiments showed that heteromerization

Additional Mechanisms of Diversity

Pharmacological and kinetic differences between native GABAB responses may additionally arise from proteins influencing receptor properties, the G-protein cycle, or the effector system. GPCRs are commonly modulated via phosphorylation of their intracellular domains resulting in a decrease in receptor to effector coupling and/or a reduction of surface expression (Tobin et al., 2008, Tsao and von Zastrow, 2000). Desensitization of GPCRs is primarily mediated by G-protein kinases (GRKs) and

Conclusions

Cloning of GABAB receptors in 1997/98 identified two GABAB(1a,2) and GABAB(1b,2) receptors with essentially indistinguishable properties in recombinant expression systems. However, a significant body of literature supports that native GABAB responses differ in their pharmacological and kinetic properties. It is emerging that some of these differences relate to a differential distribution of GABAB(1a,2) and GABAB(1b,2) receptors to axonal and dendritic compartments, which will expose them to

Acknowledgments

We would like to thank M. Gassmann, K. Ivankova, and M. Rajalu for comments on the manuscript. Our work is supported by the Swiss Science Foundation (Grant 3100A0-117816), the Fridericus Stiftung, and the European Community’s 7th Framework Programme (FP7/2007–2013) under Grant Agreement 201714.

Conflict of Interest Statement: The authors have no conflict of interest.

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