title: A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling.
abstract: Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, Montpellier, France CNRS, UMR-5203, Montpellier, France Université de Montpellier, Montpellier, France.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango-Lievano
authors.affiliation: Istanbul Medipol University, School of Engineering and Natural Sciences, Istanbul, Turkey.
authors.forename: Ozge
authors.initials: O
authors.lastname: Sensoy
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, Montpellier, France CNRS, UMR-5203, Montpellier, France Université de Montpellier, Montpellier, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Borie
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, Montpellier, France CNRS, UMR-5203, Montpellier, France Université de Montpellier, Montpellier, France.
authors.forename: Maithé
authors.initials: M
authors.lastname: Corbani
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, Montpellier, France CNRS, UMR-5203, Montpellier, France Université de Montpellier, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guillon
authors.affiliation: Unit of Neurobiology and Molecular Pharmacology, INSERM U573, Centre Paul Broca, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sokoloff
authors.affiliation: Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.affiliation: Inserm, U1191, Institute of Functional Genomics, Montpellier, France CNRS, UMR-5203, Montpellier, France Université de Montpellier, Montpellier, France freddy.jeanneteau@igf.cnrs.fr.
authors.forename: Freddy
authors.identifier: http://orcid.org/0000-0002-9606-2892
authors.initials: F
authors.lastname: Jeanneteau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010168:Palmitates / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D021381:Protein Transport; D050637:Receptors, Dopamine D3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C493593:DRD3 protein, human; C492009:GIPC1 protein, human; D010168:Palmitates; D050637:Receptors, Dopamine D3