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J. Biol. Chem., Vol. 281, Issue 40, 29669-29674, October 6, 2006

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RGS2 Inhibits the Epithelial Ca²⁺ Channel TRPV6^*

Joost P. Schoeber, Catalin N. Topala, Xinhua Wang, Robin J. Diepens, Tim T. Lambers, Joost G. Hoenderop, and René J. Bindels¹

From the Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands and the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040

The epithelial Ca²⁺ channels TRPV5 and TRPV6 constitute the apical Ca²⁺ entry pathway in the process of active Ca²⁺ (re)absorption. By yeast two-hybrid and glutathione S-transferase pulldown analysis we identified RGS2 as a novel TRPV6-associated protein. RGS proteins determine the inactivation kinetics of heterotrimeric G-protein-coupled receptor (GPCR) signaling by regulating the GTPase activity of G subunits. Here we demonstrate that TRPV6 interacts with the NH₂-terminal domain of RGS2 in a Ca²⁺-independent fashion and that overexpression of RGS2 reduces the Na⁺ and Ca²⁺ current of TRPV6 but not that of TRPV5-transfected human embryonic kidney 293 (HEK293) cells. In contrast, overexpression of the deletion mutant N-RGS2, lacking the NH₂-terminal domain of RGS2, in TRPV6-expressing HEK293 cells did not show this inhibition. Furthermore, cell surface biotinylation indicated that the inhibitory effect of RGS2 on TRPV6 activity is not mediated by differences in trafficking or retrieval of TRPV6 from the plasma membrane. This effect probably results from the direct interaction between RGS2 and TRPV6, affecting the gating properties of the channel. Finally, the scaffolding protein spinophilin, shown to recruit RGS2 and regulate GPCR-signaling via G, did not affect RGS2 binding and electrophysiological properties of TRPV6, indicating a GPCR-independent mechanism of TRPV6 regulation by RGS2.

Received for publication, June 29, 2006 , and in revised form, August 7, 2006.

^* This work was supported by the Dutch Organization of Scientific Research (NWO-ALW 814.02.001 and Zon-MW 016.006.001). 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.

¹ To whom correspondence should be addressed. E-mail: R.Bindels{at}ncmls.ru.nl.

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