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  • Review Article
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Regulation of neuronal GABAB receptor functions by subunit composition

Nature Reviews Neuroscience volume 13, pages 380–394 (2012)Cite this article

Subjects

Key Points

  • GABAB receptors (GABABRs) are the G protein-coupled receptors for the inhibitory neurotransmitter GABA. Activation of these receptors is involved in pre- and postsynaptic inhibition, regulation of Ca2+ and K+ channels and rhythmic network activity.

  • GABABRs are composed of principal GABAB1a, GABAB1b and GABAB2 subunits, which form the core of the receptor, and auxiliary KCTD8, KCTD12, KCTD12b and KCTD16 subunits, which differentially modulate receptor properties. Principal subunits form functional GABAB(1a,2) and GABAB(1b,2) heterodimers that form higher-order oligomers and bind tetramers of KCTD proteins.

  • The principal subunits regulate the surface expression and the axonal versus dendritic distribution of GABABRs, whereas the auxiliary subunits determine agonist potency and the kinetics of the receptor response.

  • Phosphorylation of the principal subunits is a prime mechanism regulating GABABR endocytosis, recycling and degradation.

  • GABABRs engage in intracellular signalling crosstalk with metabotropic and NMDA-type glutamate receptors, allowing integration of inhibitory and excitatory signals at a cellular level.

  • GABABRs are implicated in a variety of neurological and psychiatric conditions. Drugs that target receptor subtypes, defined by the KCTD proteins present, may allow more-specific therapeutic interference of GABABR-mediated signalling.

Abstract

GABAB receptors (GABABRs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the CNS. In the past 5 years, notable advances have been made in our understanding of the molecular composition of these receptors. GABABRs are now known to comprise principal and auxiliary subunits that influence receptor properties in distinct ways. The principal subunits regulate the surface expression and the axonal versus dendritic distribution of these receptors, whereas the auxiliary subunits determine agonist potency and the kinetics of the receptor response. This Review summarizes current knowledge on how the subunit composition of GABABRs affects the distribution of these receptors, neuronal processes and higher brain functions.

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Figure 1: GABAB receptor subunit composition.
Figure 2: GABAB receptor downstream effectors and their physiological roles.
Figure 3: Neuronal functions regulated by GABAB1 isoforms.
Figure 4: Phosphorylation of principal GABAB receptor subunits at serine residues regulates surface availability and effector coupling.
Figure 5: Intracellular signalling crosstalk between GABAB and glutamate receptors.

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Acknowledgements

We thank H.-R. Brenner and K. Kaupmann for critical comments on this manuscript. We gratefully acknowledge the support of the Swiss Science Foundation (31003A-133124 and CRSII3_136210), the National Center of Competences in Research (NCCR) 'Synapsy, Synaptic Bases of Mental Diseases' and the European Community's seventh Framework Program (FP7/2007-2013) under Grant Agreement 201714.

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  1. Department of Biomedicine, Institute of Physiology, University of Basel, Klingelbergstr. 50–70, Basel, 4056, Switzerland

    Martin Gassmann & Bernhard Bettler

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  1. Martin Gassmann
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Correspondence to Martin Gassmann or Bernhard Bettler.

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Glossary

G protein-coupled receptors

(GPCRs). Seven transmembrane domain proteins that respond to various extracellular ligands and sensory stimuli by activation of heterotrimeric G proteins.

Venus fly-trap domain

(VFTD). Large extracellular ligand-binding domain of family C G protein-coupled receptors that is formed of two lobes and a flexible hinge. Ligand binding favours the closed state and leads to receptor activation.

Desensitization

A decrease in the cellular response subsequent to continuous or repetitive receptor stimulation by agonist.

Regulator of G protein signalling proteins

(RGS proteins). Diverse family of cytosolic proteins binding to the activated form of Gα and increasing its GTPase activity.

Allosteric interaction

An interaction that regulates the function of a protein through induction of a conformational change.

Silent synapses

Glutamatergic synapses that contain postsynaptic NMDA-type receptors but no AMPA-type receptors (AMPARs). Silent synapses can incorporate AMPARs and become functional during synaptic plasticity processes.

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Gassmann, M., Bettler, B. Regulation of neuronal GABAB receptor functions by subunit composition. Nat Rev Neurosci 13, 380–394 (2012). https://doi.org/10.1038/nrn3249

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