title: Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein.
abstract: Striatal dopamine D2 receptor (D2R) relies upon G protein- and β-arrestin-dependent signaling pathways to convey its action on motor control and behavior. Considering that D2R activation inhibits Akt in the striatum and that huntingtin physiological functions are affected by Akt phosphorylation, we sought to investigate whether D2R-mediated signaling could regulate huntingtin phosphorylation. We demonstrate that D2R activation decreases huntingtin phosphorylation on its Akt site. This dephosphorylation event depends upon the Gαi-dependent engagement of specific members of the protein phosphatase metallo-dependent (PPM/PP2C) family and is independent of β-arrestin 2. These observations identify the PPM/PP2C family as a mediator of G protein-coupled receptor signaling and thereby suggest a novel mechanism of dopaminergic signaling.
authors.affiliation: Departments of Cell Biology, Neurobiology Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Marion
authors.affiliation: Departments of Cell Biology, Neurobiology Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Nikhil M
authors.initials: NM
authors.lastname: Urs
authors.affiliation: Departments of Cell Biology, Neurobiology Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Peterson
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval/IUSMQ, Québec G1J 2G3, Canada.
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.affiliation: Department of Neuroscience, Italian Institute of Technology, 16163 Genova, Italy.
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval/IUSMQ, Québec G1J 2G3, Canada.
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.affiliation: Departments of Cell Biology, Neurobiology Duke University Medical Center, Durham, North Carolina 27710; Departments of Medicine, Neurobiology Duke University Medical Center, Durham, North Carolina 27710; Neurobiology Duke University Medical Center, Durham, North Carolina 27710. Electronic address: marc.caron@dm.duke.edu.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D017448:Receptors, Dopamine D2; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases
keywords: Akt; Arrestin; Dopamine D2 Receptor; Dopamine Receptors; G Protein-coupled Receptors (GPCR); G Proteins; Huntingtin; PP2C; Phosphatase