Neural Cell Adhesion Molecule Modulates Dopaminergic Signaling and Behavior by Regulating Dopamine D2Receptor Internalization

Abstract

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 D₂R signaling as a result of impaired D₂R internalization. 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.