DARPP-32 40 years later

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein with an apparent Mr of 32,000), now also known as phosphatase 1 regulatory subunit 1B (PPP1R1B), is a potent inhibitor protein (PP1, PPP1) when phosphorylated at Thr34 by cAMP-dependent kinase (PKA). exhibits remarkable regional distribution in brain, roughly similar to that dopamine innervation. Its discovery was culmination the long-standing effort Paul Greengard understand mechanisms through which neurotransmitters such exert their effects on target neurons. particularly enriched striatal projection neurons where it regulated numerous signals integrates amplifies responses many stimuli. Molecular studies have revealed its regulation function are more complex than anticipated. It multiple sites several kinases modulate properties. Primarily, PP1, whereas Thr75 Cdk5 inhibits PKA. Phosphorylation serine residues CK1 CK2 modulates intracellular localization sensitivity or phosphatases. Modeling provide evidence signaling pathways including endowed strong robustness bistable properties favoring switch-like responses. Thus combined set other distinct molecules plays key role characteristic physiological these