RESUMO
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.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dopamina/metabolismo , Sistema Límbico/enzimologia , Receptores de Dopamina D3/metabolismo , Transmissão Sináptica/fisiologia , Animais , Sítios de Ligação/fisiologia , Ligação Competitiva/efeitos dos fármacos , Ligação Competitiva/fisiologia , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/química , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Sistema Límbico/ultraestrutura , Masculino , Camundongos , Camundongos Knockout , Núcleo Accumbens/enzimologia , Fosforilação , Estrutura Terciária de Proteína/fisiologia , Ratos , Ratos Wistar , Receptores de Dopamina D3/química , Receptores de Dopamina D3/genética , Membranas Sinápticas/metabolismo , Membranas Sinápticas/ultraestruturaRESUMO
Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.
