Cdk5 inhibits PKA and ERK signaling pathways in a negative feedback manner. PKA and Cdk5 act on the same downstream target, DARPP-32, resulting in opposing effects on dopaminergic signaling. Dopamine acutely activates PKA phosphorylation of DARPP-32,72 which enhances dopaminergic signaling.71 Repeated stimulation of dopamine receptors activates Cdk5 phosphorylation of DARPP-32,132 which inhibits dopaminergic signaling.73 Thus, the balance between PKA and Cdk5 activity and phosphorylation of DARPP-32 determines the overall level of dopaminergic signaling. NGF130 and BDNF131 activate ERK, which increases p35 transcription and Cdk5 activity.130 Cdk5 inhibits MEK and ERK activity and may act to limit excessive activation of ERK.138
