Beyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases
- 1 Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
- 2 Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA
- 3 Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA
- 4 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA
- 5 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
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.
Keywords: phosphorylation, protein phosphatase, protein kinase A, calcineurin, DARPP-32, ARPP-21, ARPP-16, RCS
Citation: Walaas SI, Hemmings HC Jr., Greengard P and Nairn AC (2011) Beyond the dopamine receptor: regulation and roles of serine/threonine protein phosphatases. Front. Neuroanat. 5:50. doi:10.3389/fnana.2011.00050
Received: 15 May 2011;
Paper pending published: 13 June 2011;
Accepted: 23 July 2011;
Published online: 26 August 2011.
Copyright: © 2011 Walaas, Hemmings, Greengard and Nairn. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
*Correspondence: Angus Clark Nairn, Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, CT 06508, USA. e-mail: email@example.com