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J. Biol. Chem., Vol. 279, Issue 18, 18887-18894, April 30, 2004

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Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation^*

Chihiro Hisatsune, Yukiko Kuroda¶, Kyoko Nakamura||, Takafumi Inoue¶||, Takeshi Nakamura||, Takayuki Michikawa¶, Akihiro Mizutani||, and Katsuhiko Mikoshiba¶||

From the Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute (BSI), 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan, the ^¶Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, 3-4-1, Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan, and the ^||Calcium Oscillation Project, ICORP, Japan Science and Technology Agency, 3 Nibancho, Chiyoda-ku, Tokyo 102-0084, Japan

Various hormonal stimuli and growth factors activate the mammalian canonical transient receptor potential (TRPC) channel through phospholipase C (PLC) activation. However, the precise mechanism of the regulation of TRPC channel activity remains unknown. Here, we provide the first evidence that direct tyrosine phosphorylation by Src family protein-tyrosine kinases (PTKs) is a novel mechanism for modulating TRPC6 channel activity. We found that TRPC6 is tyrosine-phosphorylated in COS-7 cells when coexpressed with Fyn, a member of the Src family PTKs. We also found that Fyn interacts with TRPC6 and that the interaction is mediated by the SH2 domain of Fyn and the N-terminal region of TRPC6 in a phosphorylation-independent manner. In addition, we demonstrated the physical association of TRPC6 with Fyn in the mammalian brain. Moreover, we showed that stimulation of the epidermal growth factor receptor induced rapid tyrosine phosphorylation of TRPC6 in COS-7 cells. This epidermal growth factor-induced tyrosine phosphorylation of TRPC6 was significantly blocked by PP2, a specific inhibitor of Src family PTKs, and by a dominant negative form of Fyn, suggesting that the direct phosphorylation of TRPC6 by Src family PTKs could be caused by physiological stimulation. Furthermore, using single channel recording, we showed that Fyn modulates TRPC6 channel activity via tyrosine phosphorylation. Thus, our findings demonstrated that tyrosine phosphorylation by Src family PTKs is a novel regulatory mechanism of TRPC6 channel activity.

Received for publication, October 14, 2003 , and in revised form, January 28, 2004.

^* This work was supported by grants from the Ministry of Education, Science, and Culture of Japan (to K. M.) and a Grant-in-aid for Young Scientists (B) (to C. H.). 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.

To whom correspondence should be addressed. Tel.: 81-03-5449-5316; Fax: 81-03-5449-5420; E-mail: chihiro{at}brain.riken.go.jp.

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