One important downstream regulator of dopaminergic signaling is DARPP-32. DARPP-32 is highly expressed in striatal neurons70 and can act as a protein kinase inhibitor or a protein phosphatase inhibitor, depending on the site of DARPP-32 phosphorylation. When PKA phosphorylates DARPP-32 on Thr-34, it serves as an inhibitor of PP-1.71 Activation of dopaminergic signaling by electrical stimulation of mouse striatal slices or by acute systemic injections of cocaine in mice increases PKA-mediated phosphorylation of DARPP-32 on Thr-34, which then inhibits PP-1 mediated dephosphorylation of PKA substrates,72 effectively amplifying dopamine-stimulated phosphorylation by PKA. Cyclin-dependent protein kinase 5 (Cdk5, discussed in the next section) phosphorylates DARPP-32 at a different site. This Thr-75 phosphorylation renders DARPP-32 an inhibitor of PKA73 and antagonizes several effects of dopamine in the striatum.
