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) 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-SY5Y cells lacking endogenous dysbindin-1. Dysbindin-1 co-transfection decreased cell surface expression of both D 3 and D 2L receptors. Address correspondence and reprint requests to Nathalie Schmieg, Institut de recherche Servier, Pole of Innovation in Neuropsychiatry, 125, chemin de Ronde, 78290 Croissy sur Seine, France. E-mail: nathalie.schmieg@crick.ac.ukAbbreviations used: AC, adenylyl cyclase; ARF6, ADP-ribosylation factor 6; BLOC-1, biogenesis of lysosome-related organelles complex 1; CHO, Chinese hamster ovary; CREB, cAMP response element-binding protein; D 2L receptor, D 2long receptor; D 2S receptor, D 2short receptor; DA, dopamine; DTNBP1, dystrobrevin binding protein 1; ERK1/2, extracellular signal-regulated kinases1/2; FCX, frontal cortex; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GASP-1, GPCR-associated sorting protein1; GSK-3b, glycogen synthase kinase 3 beta; HEK293, human embryonic kidney 293; h, human; MbCD, methylbcyclodextrine; MAPK, mitogen-activated protein kinases; PBS, phosphate buffered solution; p, phospho; Ser, serine; SPA, scintillation proximity assay; TBST, tris buffered saline with tween; Thr, threonine.

The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans

“…Specifically, D3 expression altered by single genetic variants of either D3 or Dys was restored to the wild-type level in both the mPFC and striatum of D3 +/− × Dys +/− double mutant mice. This pattern is consistent with that found in a recent in vitro study, showing that Dys might also influence the expression of D3 receptors [61]. In contrast, D3/Dys genetic interaction rescued Dys expression to the wild-type level in the striatum but not in the PFC.…”

Dysbindin-1 Involvement in the Etiology of Schizophrenia

“…Dysbindin-1 deficiency in the brain reduced Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) expression and signaling in medial prefrontal cortex, while chronic D2R agonist treatment reversed the changes in signaling [ 46 ]. Additionally, Dysbindin-1 reduced dopamine-induced adenylate cylase/cAMP signaling and phosphorylation of protein kinase B/glycogen synthase kinase-3β (Akt/GSK3β) and extracellular signal-regulated kinase1/2 (ERK 1/2) [ 85 ]. Hence, reduced expression of dysbindin-1 in the brain of schizophrenic patients may decrease dopaminergic signaling, supporting its link to the etiology of schizophrenia.…”

Abnormalities of Dopamine D3Receptor Signaling in the Diseased Brain

“… 95 Similarly, via caveolin/clathrin-mediated D 3 R internalization, dysbindin-1 reduces the magnitude and potency of DA-induced cAMP production and phosphorylation of ERK1/2 and Akt. 99 Notably, dysbindin-1 is a candidate gene for schizophrenia. Palmitoylation is another posttranslational modification that can regulate D 3 R activity.…”