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J. Biol. Chem., Vol. 282, Issue 40, 29563-29573, October 5, 2007

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Snapin, a New Regulator of Receptor Signaling, Augments _1A-Adrenoceptor-operated Calcium Influx through TRPC6^*

From the Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan

Activation of G_q-protein-coupled receptors, including the _1A-adrenoceptor (_1A-AR), causes a sustained Ca²⁺ influx via receptor-operated Ca²⁺ (ROC) channels, following the transient release of intracellular Ca²⁺. Transient receptor potential canonical (TRPC) channel is one of the candidate proteins constituting the ROC channels, but the precise mechanism linking receptor activation to increased influx of Ca²⁺ via TRPCs is not yet fully understood. We identified Snapin as a protein interacting with the C terminus of the _1A-AR. In receptor-expressing PC12 cells, co-transfection of Snapin augmented _1A-AR-stimulated sustained increases in intracellular Ca²⁺ ([Ca²⁺]_i) via ROC channels. By altering the Snapin binding C-terminal domain of the _1A-AR or by reducing cellular Snapin with short interfering RNA, the sustained increase in [Ca²⁺]_i in Snapin-_1A-AR co-expressing PC12 cells was attenuated. Snapin co-immunoprecipitated with TRPC6 and _1A-AR, and these interactions were augmented upon _1A-AR activation, increasing the recruitment of TRPC6 to the cell surface. Our data suggest a new receptor-operated signaling mechanism where Snapin links the _1A-AR to TRPC6, augmenting Ca²⁺ influx via ROC channels.

Received for publication, March 9, 2007 , and in revised form, August 6, 2007.

^* This work was supported in part by grant-in-aid for scientific research from the Japan Society of the Promotion of Science (to F. S. and I. M.) and by the 21st Center of Excellence research program (Medical Science). 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 Methods and Figs. 1-4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-776-61-8328; Fax: 81-776-61-8130; E-mail: muramatu{at}u-fukui.ac.jp.

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