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Science 22 October 2004:
Vol. 306. no. 5696, pp. 698 - 701
DOI: 10.1126/science.1099961
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Reports

A Network of Control Mediated by Regulator of Calcium/Calmodulin-Dependent Signaling

S. V. Rakhilin,1 P. A. Olson,2 A. Nishi,1,3 N. N. Starkova,1 A. A. Fienberg,1,4 A. C. Nairn,1,5* D. J. Surmeier,2* P. Greengard1*

Calmodulin (CaM) is a major effector for the intracellular actions of Ca2+ in nearly all cell types. We identified a CaM-binding protein, designated regulator of calmodulin signaling (RCS). G protein–coupled receptor (GPCR)–dependent activation of protein kinase A (PKA) led to phosphorylation of RCS at Ser55 and increased its binding to CaM. Phospho-RCS acted as a competitive inhibitor of CaM-dependent enzymes, including protein phosphatase 2B (PP2B, also called calcineurin). Increasing RCS phosphorylation blocked GPCR- and PP2B-mediated suppression of L-type Ca2+ currents in striatal neurons. Conversely, genetic deletion of RCS significantly increased this modulation. Through a molecular mechanism that amplifies GPCR- and PKA-mediated signaling and attenuates GPCR- and PP2B-mediated signaling, RCS synergistically increases the phosphorylation of key proteins whose phosphorylation is regulated by PKA and PP2B.

1 Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY 10021, USA.
2 Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3 Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.
4 Intra-Cellular Therapies Incorporated, Audubon Biomedical Science and Technology Park, New York, NY 10032, USA.
5 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.

* To whom correspondence should be addressed. E-mail: angus.nairn{at}yale.edu; j-surmeier{at}northwestern.edu; greengard{at}rockefeller.edu

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