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Mol Psychiatry. 2016 Apr;21(4):480-90. doi: 10.1038/mp.2015.72. Epub 2015 Jun 2.

GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper.

Author information

1
INSERM, U1016, Institut Cochin, Paris, France.
2
CNRS, UMR8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, France.
4
Université Paris Diderot, Sorbonne Paris Cité, France.
5
Institut du Fer a Moulin, INSERM UMR-S 839, Université Pierre et Marie Curie, Paris, France.
6
INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
7
INSERM U952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des Maladies du Système nerveux Central, Paris, France.
8
Department of Psychiatry, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.
9
Department of Biomedicine, University of Basel, Basel, Switzerland.

Abstract

Endoplasmic reticulum (ER) release and cell-surface export of many G protein-coupled receptors (GPCRs) are tightly regulated. For gamma-aminobutyric acid (GABA)B receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell-surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gatekeepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function.

PMID:
26033241
PMCID:
PMC4828513
DOI:
10.1038/mp.2015.72
[Indexed for MEDLINE]
Free PMC Article

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