DARPP-32 Phosphorylation

Dopamine- and cAMP-Regulated Phosphoprotein, Mr 32 kDa (DARPP-32), a member of the protein phosphatase inhibitor 1 family, is a cytosolic protein that is selectively enriched in neostriatal medium spiny neurons. Traditionally, DARPP-32 has been considered a major dopamine (DA)-centered signaling molecule as it is needed for DA to exert most of its effects. DARPP-32 has been shown to function as either a kinase or phosphatase inhibitor, depending upon its phosphorylation state. DARPP-32, when phosphorylated at Thr34, acts as a potent inhibitor of Protein Phosphatase 1 (PP1). DA, acting through D1-like receptors, stimulates Protein Kinase A (PKA)-mediated phosphorylation of DARPP-32 at Thr34. However, DA binding to D2-like receptors will reduce DARPP-32 Thr34 phosphorylation by inhibiting PKA and activating the protein phosphatase Calcineurin. Phosphorylation of DARPP-32 at Thr34 is also facilitated by the phosphorylation of two serine residues, Ser97 and Ser130, which are phosphorylated by Casein Kinase 2 (CK2) and CK1, respectively. Phosphorylated Ser97 increases the rate of PKA-mediated Thr34 phosphorylation, and phosphorylated Ser130 decreases the rate at which Calcineurin dephosphorylates phosphorylated Thr34. By contrast, DARPP-32 will act as kinase inhibitor when phosphorylated at Thr75. Cyclin-Dependent-Like Kinase 5 (CDK5) phosphorylates DARPP-32 at Thr75, converting it into an inhibitor of PKA, reducing the ability of PKA to phosphorylate it substrates including DARPP-32 at Thr34.

In addition to DA, several other neurotransmitters that regulate the excitability of dopaminoceptive neurons, such as glutamate, GABA, opiates, and adenosine, also signal through DARPP-32 in medium spiny neurons. The convergence of a large number of signaling pathways onto DARPP-32 in these neurons suggest that this molecule is important for integrating the vast amount of information that enters the neostriatum and ensuring that a logical neural response is produced.