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Extrasynaptic GABAA Receptors: Subunit Composition, Distribution, and Regulation

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Extrasynaptic GABAA Receptors

Part of the book series: The Receptors ((REC,volume 27))

Abstract

Among the multiple GABAA receptor (GABAAR) subtypes that are assembled from the 18 subunits encoded in the mammalian genome, several of them, notably those containing the subunits α4, α5, α6, and δ are preferentially located outside of the postsynaptic density and are activated tonically by GABA. Owing to their subunit composition, these extrasynaptic GABAAR have specific functional properties and pharmacological profiles that distinguish them from “postsynaptic” receptors. In this chapter, we summarize anatomical, developmental, and cell biological evidence that extrasynaptic GABAAR represent a specialized subset of GABAAR with specific functional roles and regulation mechanisms. Anatomically, the regional and cellular distribution of the subunits forming extrasynaptic GABAAR explains their enrichment in cerebellum, thalamus, hippocampus, dentate gyrus, striatum, olfactory bulb, and possibly spinal cord. Little is known about the ontogeny of these receptors during central nervous system (CNS) development and neurogenesis, but it is likely that extrasynaptic receptors on progenitor cells and differentiating neurons differ from their adult counterparts, notably owing to late onset of α6 and δ subunit expression. On the cell biological level, the extrasynaptic localization of receptors containing the α4, α5, and δ subunits depends on structural motifs that either prevent interaction with the postsynaptic scaffolding molecule gephyrin or allow interaction with radixin, a member of the ezrin/radixin/moesin family of actin-interacting proteins. Importantly, there is evidence indicating that regulation of GABAAR trafficking and cell-surface expression, mediated in part by protein phosphorylation mechanisms, allows for rapid changes in the ratio of extrasynaptic/postsynaptic receptors upon physiological and pathophysiological stimuli. A better understanding of the subcellular localization and regulation of extrasynaptic GABAAR will be required to unravel their multiple contributions to the control of neuronal network activity and behavior.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, 8057, Zürich, Switzerland

    Jean-Marc Fritschy

  2. Department of Neuroscience Rita Levi Montalcini, University of Turin, 10126, Turin, Italy

    Patrizia Panzanelli

Authors
  1. Jean-Marc Fritschy
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  2. Patrizia Panzanelli
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Corresponding author

Correspondence to Jean-Marc Fritschy .

Editor information

Editors and Affiliations

  1. Neuroscience and Mental Health Research Institute, Institute of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, United Kingdom

    Adam C. Errington

  2. Dept. of Physiology & Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

  3. School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Vincenzo Crunelli

Conclusions

Conclusions

This brief overview highlights how most of the knowledge available to date on extrasynaptic GABAAR is derived from pharmacological and functional studies, whereas much remains to be done to elucidate their precise cellular and subcellular localization, their contribution to CNS development, and the mechanisms underlying their regulation under physiological and pathophysiological conditions.

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Fritschy, JM., Panzanelli, P. (2014). Extrasynaptic GABAA Receptors: Subunit Composition, Distribution, and Regulation. In: Errington, A., Di Giovanni, G., Crunelli, V. (eds) Extrasynaptic GABAA Receptors. The Receptors, vol 27. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1426-5_2

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