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

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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Molecular Psychiatry, Nature Publishing Group, 2016, 21, pp.480-490. 〈10.1038/mp.2015.72〉
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Stéphane Doly, Hamasseh Shirvani, Gabriel Gäta, Frank Meye, Michel-Boris Emerit, et al.. GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper. Molecular Psychiatry, Nature Publishing Group, 2016, 21, pp.480-490. 〈10.1038/mp.2015.72〉. 〈inserm-01153352〉

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