title: 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.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: S
authors.initials: S
authors.lastname: Doly
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: H
authors.initials: H
authors.lastname: Shirvani
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.|Université Paris Diderot, Sorbonne Paris Cité, France.
authors.forename: G
authors.initials: G
authors.lastname: Gäta
authors.affiliation: Institut du Fer a Moulin, INSERM UMR-S 839, Université Pierre et Marie Curie, Paris, France.
authors.forename: F J
authors.initials: FJ
authors.lastname: Meye
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France.|INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: M-B
authors.initials: MB
authors.lastname: Emerit
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: H
authors.initials: H
authors.lastname: Enslen
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: L
authors.initials: L
authors.lastname: Achour
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: L
authors.initials: L
authors.lastname: Pardo-Lopez
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France.|INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: S-K
authors.initials: SK
authors.lastname: Yang
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France.|INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Armand
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France.|INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Gardette
authors.affiliation: INSERM U952, CNRS UMR 7224, Université Pierre et Marie Curie, Physiopathologie des Maladies du Système nerveux Central, Paris, France.|Department of Psychiatry, Douglas Hospital Research Center, McGill University, Montreal, QC, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Giros
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Institut du Fer a Moulin, INSERM UMR-S 839, Université Pierre et Marie Curie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Mameli
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, France.|INSERM U894, Centre de Psychiatrie et Neurosciences, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Darmon
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: S
authors.initials: S
authors.lastname: Marullo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055503:Protein Multimerization; D021122:Protein Subunits; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C499863:PRAF2 protein, human; D021122:Protein Subunits; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid