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TRPC channel activation by extracellular thioredoxin

Xu, Shang-Zhong; Sukumar, Piruthivi; Zeng, Fanning; Li, Jing; Jairaman, Amit; English, Anne; Naylor, Jacqueline; Ciurtin, Coziana; Majeed, Yasser; Milligan, Carol J.; Bahnasi, Yahya M.; Al-Shawaf, Eman; Porter, Karen E.; Jiang, Lin-Hua; Emery, Paul; Sivaprasadarao, Asipu; Beech, David J.

Authors

Shang-Zhong Xu

Piruthivi Sukumar

Fanning Zeng

Jing Li

Amit Jairaman

Anne English

Jacqueline Naylor

Coziana Ciurtin

Yasser Majeed

Carol J. Milligan

Yahya M. Bahnasi

Eman Al-Shawaf

Karen E. Porter

Lin-Hua Jiang

Paul Emery

Asipu Sivaprasadarao

David J. Beech



Abstract

Mammalian homologues of Drosophila melanogaster transient receptor potential (TRP) are a large family of multimeric cation channels that act, or putatively act, as sensors of one or more chemical factor. Major research objectives are the identification of endogenous activators and the determination of cellular and tissue functions of these channels. Here we show the activation of TRPC5 (canonical TRP 5) homomultimeric and TRPC5-TRPC1 heteromultimeric channels by extracellular reduced thioredoxin, which acts by breaking a disulphide bridge in the predicted extracellular loop adjacent to the ion-selectivity filter of TRPC5. Thioredoxin is an endogenous redox protein with established intracellular functions, but it is also secreted and its extracellular targets are largely unknown. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis, an inflammatory joint disease that disables millions of people worldwide. We show that TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, that endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin, and that blockade of the channels enhances secretory activity and prevents the suppression of secretion by thioredoxin. The data indicate the presence of a previously unrecognized ion-channel activation mechanism that couples extracellular thioredoxin to cell function

Journal Article Type Article
Publication Date 2008-02
Journal Nature
Print ISSN 0028-0836
Electronic ISSN 1476-4687
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 451
Issue 7174
Pages 69-72
APA6 Citation Xu, S., Sukumar, P., Zeng, F., Li, J., Jairaman, A., English, A., …Beech, D. J. (2008). TRPC channel activation by extracellular thioredoxin. Nature, 451(7174), (69-72). doi:10.1038/nature06414. ISSN 0028-0836
DOI https://doi.org/10.1038/nature06414
Keywords Animals, Arthritis, Arthritis, Rheumatoid, Cell Line, Disease, Disulfides, Drosophila, Electric Conductivity, Family, Humans, Oxidation-Reduction, Patch-Clamp Techniques, Rabbits, Research, Research Support, TRPC Cation Channels, Thioredoxins, agonists, c
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