Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is central to synaptic transmission. Here we show that synaptic CaMKIIalpha binds to the N-terminal region of the third intracellular loop of the limbic dopamine D3 receptor (D3R). This binding is Ca(2+) sensitive and is sustained by autophosphorylation of CaMKII, providing an unrecognized route for the Ca(2+)-mediated regulation of D3Rs. The interaction of CaMKIIalpha 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, CaMKIIalpha is recruited to D3Rs by rising Ca(2+) to increase the CaMKIIalpha-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 CaMKIIalpha as a recruitable regulator of dopamine receptor function. By binding and phosphorylating limbic D3Rs, CaMKIIalpha modulates dopamine signaling and psychomotor function in an activity-dependent manner.