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.

ACKNOWLEDGMENTS

The work was supported by the Fondation pour la Recherche Médicale, the Fondation de France, and the French Ministry of Research.

We thank M. Asari for figure editing.

M.A.-L., P.S., and F.J. conceived all experiments. O.S. and H.W. designed the computational experiments. M.A.-L. and F.J. collected biochemical data. M.A.-L. and M.C. produced time-lapse fluorescence imaging data. G.G. and A.B. did binding and cAMP experiments. O.S. performed in silico simulation studies. M.A.-L. and F.J. wrote the manuscript, with contributions from O.S., H.W., and P.S.

We declare no competing interests.

Notes

The Unit of Neurobiology and Molecular Pharmacology, INSERM U573 research unit, no longer exists and has been integrated into INSERM UMR894, Center for Psychiatry and Neuroscience, Paris, France.