title: Dysbindin-1 modifies signaling and cellular localization of recombinant, human D₃ and D₂ receptors.
abstract: Dystrobrevin binding protein-1 (dysbindin-1), a candidate gene for schizophrenia, modulates cognition, synaptic plasticity and frontocortical circuitry and interacts with glutamatergic and dopaminergic transmission. Loss of dysbindin-1 modifies cellular trafficking of dopamine (DA) D2 receptors to increase cell surface expression, but its influence upon signaling has never been characterized. Further, the effects of dysbindin-1 upon closely related D3 receptors remain unexplored. Hence, we examined the impact of dysbindin-1 (isoform A) co-expression on the localization and coupling of human D2L and D3 receptors stably expressed in Chinese hamster ovary or SH-SY5Y cells lacking endogenous dysbindin-1. Dysbindin-1 co-transfection decreased cell surface expression of both D3 and D2L receptors. Further, while their affinity for DA was unchanged, dysbindin-1 reduced the magnitude and potency of DA-induced adenylate cylase recruitment/cAMP production. Dysbindin-1 also blunted the amplitude of DA-induced phosphorylation of ERK1/2 and Akt at both D2L and D3 receptors without, in contrast to cAMP, affecting the potency of DA. Interference with calveolin/clathrin-mediated processes of internalization prevented the modification by dysbindin-1 of ERK1/2 and adenylyl cyclase stimulation at D2L and D3 receptors. Finally, underpinning the specificity of the influence of dysbindin-1 on D2L and D3 receptors, dysbindin-1 did not modify recruitment of adenylyl cyclase by D1 receptors. These observations demonstrate that dysbindin-1 influences cell surface expression of D3 in addition to D2L receptors, and that it modulates activation of their signaling pathways. Accordingly, both a deficiency and an excess of dysbindin-1 may be disruptive for dopaminergic transmission, supporting its link to schizophrenia and other CNS disorders. Dysbindin-1, a candidate gene for schizophrenia, alters D2 receptors cell surface expression. We demonstrate that dysbindin-1 expression also influences cell surface levels of D3 receptors. Further, Dysbindin-1 reduces DA-induced adenylate cylase recruitment/cAMP production and modifies major signaling pathways (Akt and extracellular signal-regulated kinases1/2 (ERK1/2)) of both D2 and D3 receptors. Dysbindin-1 modulates thus D2 and D3 receptor signaling, supporting a link to schizophrenia.
authors.affiliation: PIT-Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schmieg
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L'Aquila, L'Aquila, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rocchi
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L'Aquila, L'Aquila, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Biotechnological and Applied Clinical Sciences Department, University of L'Aquila, L'Aquila, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maggio
authors.affiliation: PIT-Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: PIT-Neuropsychiatry, Institut de Recherches Servier, Centre de Recherches de Croissy, Croissy-sur-Seine, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Mannoury la Cour
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000262:Adenylyl Cyclases; D004298:Dopamine
keywords: D2 receptor; D3 receptor; dopamine; dysbindin-1; internalization; schizophrenia