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Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions

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Abstract

Rationale

Gamma-aminobutyric acid type A receptors (GABAARs) are the principal mediators of inhibitory transmission in the mammalian central nervous system. GABAARs can be localized at post-synaptic inhibitory specializations or at extrasynaptic sites. While synaptic GABAARs are activated transiently following the release of GABA from presynaptic vesicles, extrasynaptic GABAARs are typically activated continuously by ambient GABA concentrations and thus mediate tonic inhibition. The tonic inhibitory currents mediated by extrasynaptic GABAARs control neuronal excitability and the strength of synaptic transmission. However, the mechanisms by which neurons control the functional properties of extrasynaptic GABAARs had not yet been explored.

Objectives

We review GABAARs, how they are assembled and trafficked, and the role phosphorylation has on receptor insertion and membrane stabilization. Finally, we review the modulation of GABAARs by neurosteroids and how GABAAR phosphorylation can influence the actions of neurosteroids.

Conclusions

Trafficking and stability of functional channels to the membrane surface are critical for inhibitory efficacy. Phosphorylation of residues within GABAAR subunits plays an essential role in the assembly, trafficking, and cell surface stability of GABAARs. Neurosteroids are produced in the brain and are highly efficacious allosteric modulators of GABAAR-mediated current. This allosteric modulation by neurosteroids is influenced by the phosphorylated state of the GABAAR which is subunit dependent, adding temporal and regional variability to the neurosteroid response. Possible links between neurosteroid actions, phosphorylation, and GABAAR trafficking remain to be explored, but potential novel therapeutic targets may exist for numerous neurological and psychological disorders which are linked to fluctuations in neurosteroid levels and GABAA subunit expression.

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Abbreviations

AP2:

Clathin adaptor protein 2

BIG2:

Brefeldin A-inhibited GDP/GTP exchange factor 2

CAML:

Calcium-modulating cyclophilin ligand

ER:

Endoplasmic reticulum

GABA:

γ-aminobutyric acid

GABAARs:

γ-aminobutyric acid type A receptors

GABARAP:

GABAAR-associated proteinA

GODZ:

Golgi-specific DHHC zinc finger protein

HAP1:

Huntingtin-associated protein 1

PKC:

Protein kinase C

THDOC:

Allotetrahydrodeoxycorticosterone

THIP- 4,5,6,7:

Tetrahydroisoxazolo[5,4-c]pyridin-3-ol

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Acknowledgments

This work was supported by a grant from the Simons Foundation #206026 to S.J.M., NIH-NINDS grants, NS051195, NS056359, NS081735 (SJM), and NIH-NIMH grant, MH097446, (PAD & SJM). SJM serves as a consultant for SAGE therapeutics and AstraZeneca, relationships that are regulated by Tufts University and do not impact on this study.

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  1. Department of Neuroscience, Tufts University School of Medicine, Boston, MA, 02111, USA

    Eydith Comenencia-Ortiz, Stephen J. Moss & Paul A. Davies

  2. Department of Neuroscience, Physiology & Pharmacology, University College London, London, WC1E 6B, UK

    Stephen J. Moss

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  1. Eydith Comenencia-Ortiz
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Correspondence to Paul A. Davies.

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Comenencia-Ortiz, E., Moss, S.J. & Davies, P.A. Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions. Psychopharmacology 231, 3453–3465 (2014). https://doi.org/10.1007/s00213-014-3617-z

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