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 Thr34 and
thereby converts DARPP-32 into a potent inhibitor of protein
phosphatase-1 (PP-1). DARPP-32 is also phosphorylated at
Thr75 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 Thr34 depends on the phosphorylation state of two serine
residues, Ser102 and Ser137, 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.
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