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J. Biol. Chem., Vol. 282, Issue 43, 31656-31665, October 26, 2007

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Regulation of RGS2 and Second Messenger Signaling in Vascular Smooth Muscle Cells by cGMP-dependent Protein Kinase^*

Patrick Osei-Owusu¹, Xiaoguang Sun¹, Ryan M. Drenan, Thomas H. Steinberg, and Kendall J. Blumer²

From the Cell Biology and Physiology and Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

RGS2, a GTPase-activating protein (GAP) for G_q, regulates vascular relaxation and blood pressure. RGS2 can be phosphorylated by type I cGMP-dependent protein kinase (cGKI), increasing its GAP activity. To understand how RGS2 and cGKI regulate vascular smooth muscle signaling and function, we identified signaling pathways that are controlled by cGMP in an RGS2-dependent manner and discovered new mechanisms whereby cGK activity regulates RGS2. We show that RGS2 regulates vasoconstrictor-stimulated Ca²⁺ store release, capacitative Ca²⁺ entry, and noncapacitative Ca²⁺ entry and that RGS2 is required for cGMP-mediated inhibition of vasoconstrictor-elicited phospholipase C activation, Ca²⁺ store release, and capacitative Ca²⁺ entry. RGS2 is degraded in vascular smooth muscle cells via the proteasome. Inhibition of cGK activity blunts RGS2 degradation. However, inactivation of the cGKI phosphorylation sites in RGS2 does not stabilize the protein, suggesting that cGK activity regulates RGS2 degradation by other mechanisms. cGK activation promotes association of RGS2 with the plasma membrane by a mechanism requiring its cGKI phosphorylation sites. By regulating GAP activity, plasma membrane association, and degradation, cGKI therefore may control a cycle of RGS2 activation and inactivation. By diminishing cGK activity, endothelial dysfunction may impair RGS2 activation, thereby blunting vascular relaxation and contributing to hypertension.

Received for publication, August 1, 2007

^* This work was supported by American Heart Association Predoctoral Fellowship 04153107Z (to R. M. D.) and National Institutes of Health Grants GM44592 and HL075632 (to K. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Movies 1-4.

¹ These two authors contributed equally to this work and are co-first authors.

² To whom correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-1668; Fax: 314-362-7463; E-mail: kblumer{at}cellbiology.wustl.edu.

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