Article abstract
Nature Chemical Biology 2, 596 - 607 (2006)
Published online: 24 September 2006 | doi:10.1038/nchembio821
Nitric oxide activates TRP channels by cysteine S-nitrosylation
Takashi Yoshida1,2,3, Ryuji Inoue4, Takashi Morii5, Nobuaki Takahashi1, Shinichiro Yamamoto1, Yuji Hara1, Makoto Tominaga2,3, Shunichi Shimizu6, Yoji Sato7 & Yasuo Mori1
Abstract
Transient receptor potential (TRP) proteins form plasma-membrane cation channels that act as sensors for diverse cellular stimuli. Here, we report a novel activation mechanism mediated by cysteine S-nitrosylation in TRP channels. Recombinant TRPC1, TRPC4, TRPC5, TRPV1, TRPV3 and TRPV4 of the TRPC and TRPV families, which are commonly classified as receptor-activated channels and thermosensor channels, induce entry of Ca2+ into cells in response to nitric oxide (NO). Labeling and functional assays using cysteine mutants, together with membrane sidedness in activating reactive disulfides, show that cytoplasmically accessible Cys553 and nearby Cys558 are nitrosylation sites mediating NO sensitivity in TRPC5. The responsive TRP proteins have conserved cysteines on the same N-terminal side of the pore region. Notably, nitrosylation of native TRPC5 upon G protein–coupled ATP receptor stimulation elicits entry of Ca2+ into endothelial cells. These findings reveal the structural motif for the NO-sensitive activation gate in TRP channels and indicate that NO sensors are a new functional category of cellular receptors extending over different TRP families.
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
- Center for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki, Aichi 444-8585, Japan.
- School of Life Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585, Japan.
- Department of Physiology, Fukuoka University, Fukuoka 814-0180, Japan.
- Institute of Advanced Energy, Kyoto University, Uji, Kyoto 611-0011, Japan.
- Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan.
- Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8510, Japan.
Correspondence to: Yasuo Mori1 e-mail: mori@sbchem.kyoto-u.ac.jp
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