Neural cell adhesion molecule modulates dopaminergic signaling and behavior by regulating dopamine D₂ receptor internalization

The dopaminergic system plays an important role in the etiology of schizophrenia, and most antipsychotic drugs exert their functions by blocking dopamine D₂ receptors (D₂Rs). Since the signaling strength mediated by D₂Rs is regulated by internalization and degradation processes, it is crucial to identify molecules that modulate D₂R localization at the cell surface. Here, we show that the neural cell adhesion molecule (NCAM) promotes D₂R internalization/desensitization and subsequent degradation via direct interaction with a short peptide in the third intracellular loop of the D₂R. NCAM deficiency in mice leads to increased numbers of D₂Rs at the cell surface and augmented D ₂R-signaling as a result of impairedD2Rinternalization. Furthermore, NCAM-deficient mice show higher sensitivity to the psychostimulant apomorphine and exaggerated activity of dopamine-related locomotor behavior. These results demonstrate that, in addition to its classical function in cell adhesion, NCAM is involved in regulating the trafficking of the neurotransmitter receptor D₂R as well as receptor-mediated signaling and behavior, thus implicating NCAM as modulator of the dopaminergic system and a potential pharmacological target for dopamine-related neurological and psychiatric disorders.