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Cdk5 is a cyclin dependent protein kinase involved in dopaminergic signaling in the neostriatal region of the brain. The role of cdk5 in dopamine responses occurs through phosphorylation of DARPP-32. Casein kinase 1 (CK1) also regulates DARPP-32 phosphorylation and dopamine signaling. The phosphorylation of DARPP-32 by cdk5 reduced dopamine signaling. Depending on its phosphorylation state, DARPP-32 inhibits either protein phosphatase 1 (PP1) or PKA. The role of mGLUR1 in this process is supported by the induction of cdk5 and CK1 activity by the mGLUR1 agonist DHPG and the subsequent phosphorylation of DARPP-32 associated with DHPG treatment of nigrostriatal neurons. CK-1 and Ckd5 inhibitors block the DHPG induced DARPP-32 phosphorylation. Dopamine exerts a positive signal that increases dopamine response by reversing phosphorylation of DARPP-32 at threonine-75. Dopamine initiates this pathway through activation of the D1 dopamine receptor, a Gs coupled GPCR, elevating cAMP and activating PKA. PKA activates protein phosphatase 2A (PP2A) which dephosphorylates DARPP-32 and increases dopamine responsiveness. This also removes the inhibition of PKA by DARPP-32, forming a positive feedback loop for further DARPP-32 inactivation by PKA. Activation of the D2 dopamine receptor has the opposite effect, shifting the DARPP-32 population toward the threonine-75 phosphorylated form. (This definition may be outdated - see the DesignNote.)
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