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J. Biol. Chem., Vol. 283, Issue 15, 10026-10036, April 11, 2008

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Isoform-specific Inhibition of TRPC4 Channel by Phosphatidylinositol 4,5-Bisphosphate^*

Ken-ichi Otsuguro¹, Jisen Tang, Yufang Tang, Rui Xiao, Marc Freichel^¶, Volodymyr Tsvilovskyy^¶, Shigeo Ito^||, Veit Flockerzi^¶, Michael X. Zhu², and Alexander V. Zholos³

From the Cardiovascular Biomedical Research Centre, School of Medicine and Dentistry, Queen's University Belfast, Belfast BT9 7BL, United Kingdom, the Department of Neuroscience and Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210, the ^¶Department of Pharmacology and Toxicology, University of Saarland, Homburg 66421, Germany, and the ^||Laboratory of Pharmacology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan

Full-length transient receptor potential (TRP) cation channel TRPC4 and shorter TRPC4β lacking 84 amino acids in the cytosolic C terminus are expressed in smooth muscle and endothelial cells where they regulate membrane potential and Ca²⁺ influx. In common with other "classical" TRPCs, TRPC4 is activated by G_q/phospholipase C-coupled receptors, but the underlying mechanism remains elusive. Little is also known about any isoform-specific channel regulation. Here we show that TRPC4 but not TRPC4β was strongly inhibited by intracellularly applied phosphatidylinositol 4,5-bisphosphate (PIP₂). In contrast, several other phosphoinositides (PI), including PI(3,4)P₂, PI(3,5)P₂, and PI(3,4,5)P₃, had no effect or even potentiated TRPC4 indicating that PIP₂ inhibits TRPC4 in a highly selective manner. We show that PIP₂ binds to the C terminus of TRPC4 but not that of TRPC4β in vitro. Its inhibitory action was dependent on the association of TRPC4 with actin cytoskeleton as it was prevented by cytochalasin D treatment or by the deletion of the C-terminal PDZ-binding motif (Thr-Thr-Arg-Leu) that links TRPC4 to F-actin through the sodium-hydrogen exchanger regulatory factor and ezrin. PIP₂ breakdown appears to be a required step in TRPC4 channel activation as PIP₂ depletion alone was insufficient for channel opening, which additionally required Ca²⁺ and pertussis toxin-sensitive G_i/o proteins. Thus, TRPC4 channels integrate a variety of G-protein-dependent stimuli, including a PIP₂/cytoskeleton dependence reminiscent of the TRPC4-like muscarinic agonist-activated cation channels in ileal myocytes.

Received for publication, August 30, 2007 , and in revised form, January 25, 2008.

^* This work was supported by Queen's University Belfast (to A. V. Z.), the Ministry of Education, Culture, Sports, Science and Technology (Mext), Japan (to S. I., and K. O.), the Deutsche Forschungsgemeinschaft (to V. F.), and National Institutes of Health and American Heart Association grants (to M. X. Z.). 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 Present address: Laboratory of Pharmacology, Dept. of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.

² To whom correspondence may be addressed: Center for Molecular Neurobiology, Ohio State University, Columbus, OH 43210. Fax: 614-292-5379; E-mail: zhu.55{at}osu.edu.

³ To whom correspondence may be addressed: Medical Biology Centre, 97 Lisburn Rd., Belfast BT9 7BL, UK. Fax: 28-9097-5775; E-mail: a.zholos{at}qub.ac.uk.

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