Dysbindin‐1 modifies signaling and cellular localization of recombinant, human D 3 and D 2 receptors

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 ) D 2 receptors to increase cell surface expression, but its influence upon signaling has never been characterized. Further, the effects of dysbindin‐1 upon closely related D 3 receptors remain unexplored. Hence, we examined the impact of dysbindin‐1 (isoform A) co‐expression on the localization and coupling of human D 2L and D 3 receptors stably expressed in Chinese hamster ovary or SH ‐ SY 5Y cells lacking endogenous dysbindin‐1. Dysbindin‐1 co‐transfection decreased cell surface expression of both D 3 and D 2L 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 ERK 1/2 and Akt at both D 2L and D 3 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 ERK 1/2 and adenylyl cyclase stimulation at D 2L and D 3 receptors. Finally, underpinning the specificity of the influence of dysbindin‐1 on D 2L and D 3 receptors, dysbindin‐1 did not modify recruitment of adenylyl cyclase by D 1 receptors. These observations demonstrate that dysbindin‐1 influences cell surface expression of D 3 in addition to D 2L 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 D 2 receptors cell surface expression. We demonstrate that dysbindin‐1 expression also influences cell surface levels of D 3 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 D 2 and D 3 receptors. Dysbindin‐1 modulates thus D 2 and D 3 receptor signaling, supporting a link to schizophrenia.