Beyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases.

TitleBeyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases.
Publication TypeJournal Article
Year of Publication2011
AuthorsWalaas SIvar, Hemmings HCaroll, Greengard P, Nairn AClark
JournalFront Neuroanat
Date Published2011

Dopamine plays an important modulatory role in the central nervous system, helping to control critical aspects of motor function and reward learning. Alteration in normal dopaminergic neurotransmission underlies multiple neurological diseases including schizophrenia, Huntington's disease, and Parkinson's disease. Modulation of dopamine-regulated signaling pathways is also important in the addictive actions of most drugs of abuse. Our studies over the last 30 years have focused on the molecular actions of dopamine acting on medium spiny neurons, the predominant neurons of the neostriatum. Striatum-enriched phosphoproteins, particularly dopamine and adenosine 3':5'-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32), regulator of calmodulin signaling (RCS), and ARPP-16, mediate pleiotropic actions of dopamine. Notably, each of these proteins, either directly or indirectly, regulates the activity of one of the three major subclasses of serine/threonine protein phosphatases, PP1, PP2B, and PP2A, respectively. For example, phosphorylation of DARPP-32 at Thr34 by protein kinase A results in potent inhibition of PP1, leading to potentiation of dopaminergic signaling at multiple steps from the dopamine receptor to the nucleus. The discovery of DARPP-32 and its emergence as a critical molecular integrator of striatal signaling will be discussed, as will more recent studies that highlight novel roles for RCS and ARPP-16 in dopamine-regulated striatal signaling pathways.

Alternate JournalFront Neuroanat
PubMed ID21904525
PubMed Central IDPMC3162284
Grant ListP01 DA010044 / DA / NIDA NIH HHS / United States
R01 NS056315 / NS / NINDS NIH HHS / United States