DARPP32, or dopamine- and cAMP-regulated phosphoprotein with an apparent molecular weight of 32 kDa, is a signaling protein that plays a crucial role in the brain, particularly in regions rich in dopaminergic nerve terminals. It is known to be a potent inhibitor of protein phosphatase 1 (PP1) when phosphorylated at Thr34 by cAMP-dependent protein kinase (PKA). DARPP32 is also phosphorylated at other sites by various kinases, which modulates its properties. For instance, phosphorylation at Thr75 by Cdk5 converts DARPP32 into an inhibitor of PKA. This dual functionality makes DARPP32 a key integrator in signal transduction pathways. DARPP-32 is involved in the regulation of a range of physiological and behavioral responses to various stimuli, including neurotransmitters like dopamine and glutamate, as well as drugs of abuse such as cocaine, amphetamine, nicotine, and caffeine. The phosphorylation state of DARPP-32 is intricately regulated, with phosphorylation at Ser102 and Ser137 by CK2 and CK1, respectively, influencing its activity. This complex regulation enables DARPP-32 to modulate the activity of PP-1 and PKA, which in turn affects electrophysiological, transcriptional, and behavioral responses. Moreover, DARPP-32 has been implicated in several psychiatric and neurological disorders, including schizophrenia, and its expression has been observed in a variety of epithelial cells beyond the central nervous system. High levels of DARPP-32 have been associated with survival in certain cancers, suggesting it may play a role in tumorigenesis and could be a potential therapeutic target.
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