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▪ Abstract Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was identified initially as a major target for dopamine and protein kinase A (PKA) in striatum. However, recent advances now indicate that regulation of the state of DARPP-32 phosphorylation provides a mechanism for integrating information arriving at dopaminoceptive neurons, in multiple brain regions, via a variety of neurotransmitters, neuromodulators, neuropeptides, and steroid hormones. Activation of PKA or PKG stimulates DARPP-32 phosphorylation at Thr<sup>34</sup> and thereby converts DARPP-32 into a potent inhibitor of protein phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at Thr<sup>75</sup> by Cdk5 and this converts DARPP-32 into an inhibitor of PKA. Thus, DARPP-32 has the unique property of being a dual-function protein, acting either as an inhibitor of PP-1 or of PKA. The state of phosphorylation of DARPP-32 at Thr<sup>34</sup> depends on the phosphorylation state of two serine residues, Ser<sup>102</sup> and Ser<sup>137</sup>, which are phosphorylated by CK2 and CK1, respectively. By virtue of its ability to modulate the activity of PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse. |
