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.
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Acknowledgements
We thank Drs M Scott (Institut Cochin), M Bouvier (Université de Montréal, Canada) and J Epelbaum (Centre de Psychiatrie et Neurosciences, Paris) for their comments; Dr L Maroteaux (Institut du Fer à Moulin, Paris) for hosting studies in mice; Dr C Labbé-Jullié (Institut Cochin) for preliminary studies; Dr E Tzavara (Unité de Physiopathologie des Maladies du Système Nerveux, Paris) for helpful discussions; the Cochin Institute imaging facility for technical support. This work was supported by grants from the Ligue Contre le Cancer, comité de l’Oise to SD; from the French Agency for AIDS Research (ANRS-09) and the Fondation pour la Recherche Médicale (Equipe FRM-2012) to SM; from the Ecole de Neuroscience de Paris and the INSERM ATIP-Avenir to MM; from the NCCR ‘Synapsy, Synaptic Bases of Mental Diseases’ to BB. SM team is member of the ‘Who-am-I’ research consortium.
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Doly, S., Shirvani, H., Gäta, G. et al. GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper. Mol Psychiatry 21, 480–490 (2016). https://doi.org/10.1038/mp.2015.72
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DOI: https://doi.org/10.1038/mp.2015.72
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