GSK-3β Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia.

INTRODUCTION: Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function. AIMS: To investigate the physical interaction and functional modulation between D1R and GSK-3β. RESULTS: D1R and GSK-3β physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3β impaired D1R activation along with a decrease in D1R-GSK-3β interaction. GSK-3β inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of β-arrestin-2. Similarly, inhibition of GSK-3β in rat PFC also resulted in impaired D1R activation and association with GSK-3β. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3β activity and D1R-GSK-3β association and decreased D1R activation in the PFC. CONCLUSIONS: The present work identified GSK-3β as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3β-regulated D1R function which may underlie D1R dysfunction in schizophrenia.