DARPP-32 40 years later

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