Activity-Dependent Modulation of Limbic Dopamine D3 Receptors by CaMKII

Ca2+/calmodulin-dependent protein kinase 11 (CaMKI I) is central to synaptic transmission. Here we show that synaptic CaMKII alpha 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 auto phosphorylation of CaMKII, providing an unrecognized route for the Ca2+-mediated regulation of D3Rs. The interaction of CaMKII alpha 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, CaMKII alpha is recruited to D3Rs by rising Ca2+ to increase the CaMKII alpha-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 CaMKIIa as a recruitable regulator of dopamine receptor function. By binding and phosphorylating limbic D3R CaMKII alpha modulates dopamine signaling and psychomotor function in an activity-dependent manner.