Activity-Dependent Modulation of Limbic Dopamine D3 Receptors by CaMKII

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is central to synaptic transmission. Here we show that synaptic CaMKIIα binds to the N-terminal region of the third intracellular loop of the limbic dopamine D3 receptor (D3R). This binding is Ca²⁺ sensitive and is sustained by autophosphorylation of CaMKII, providing an unrecognized route for the Ca²⁺-mediated regulation of D3Rs. The interaction of CaMKIIα with D3Rs transforms D3Rs into a biochemical substrate of the kinase and promotes the kinase to phosphorylate D3Rs at a selective serine site (S229). In accumbal neurons in vivo, CaMKIIα is recruited to D3Rs by rising Ca²⁺ to increase the CaMKIIα-mediated phosphorylation of D3Rs, thereby transiently inhibiting D3R efficacy. Notably, the D3R inhibition is critical for integrating dopamine signaling to control behavioral sensitivity to the psychostimulant cocaine. Our data identify CaMKIIα as a recruitable regulator of dopamine receptor function. By binding and phosphorylating limbic D3Rs, CaMKIIα modulates dopamine signaling and psychomotor function in an activity-dependent manner.