Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation

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

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)18887-18894
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
Publication statusPublished - 2004 Apr 30
Externally publishedYes

Fingerprint

Phosphorylation
src-Family Kinases
Tyrosine
Protein-Tyrosine Kinases
COS Cells
Type C Phospholipases
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Transient Receptor Potential Channels
Brain
Intercellular Signaling Peptides and Proteins
src Homology Domains
Chemical activation
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hisatsune, C., Kuroda, Y., Nakamura, K., Inoue, T., Nakamura, T., Michikawa, T., ... Mikoshiba, K. (2004). Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation. Journal of Biological Chemistry, 279(18), 18887-18894. https://doi.org/10.1074/jbc.M311274200

Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation. / Hisatsune, Chihiro; Kuroda, Yukiko; Nakamura, Kyoko; Inoue, Takafumi; Nakamura, Takeshi; Michikawa, Takayuki; Mizutani, Akihiro; Mikoshiba, Katsuhiko.

In: Journal of Biological Chemistry, Vol. 279, No. 18, 30.04.2004, p. 18887-18894.

Research output: Contribution to journalArticle

Hisatsune, C, Kuroda, Y, Nakamura, K, Inoue, T, Nakamura, T, Michikawa, T, Mizutani, A & Mikoshiba, K 2004, 'Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation', Journal of Biological Chemistry, vol. 279, no. 18, pp. 18887-18894. https://doi.org/10.1074/jbc.M311274200
Hisatsune C, Kuroda Y, Nakamura K, Inoue T, Nakamura T, Michikawa T et al. Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation. Journal of Biological Chemistry. 2004 Apr 30;279(18):18887-18894. https://doi.org/10.1074/jbc.M311274200
Hisatsune, Chihiro ; Kuroda, Yukiko ; Nakamura, Kyoko ; Inoue, Takafumi ; Nakamura, Takeshi ; Michikawa, Takayuki ; Mizutani, Akihiro ; Mikoshiba, Katsuhiko. / Regulation of TRPC6 Channel Activity by Tyrosine Phosphorylation. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 18. pp. 18887-18894.
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