TRPC channel activation by extracellular thioredoxin

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 AlShawaf, Karen E Porter, Lin-Hua Jiang, Paul Emery, Asipu Sivaprasadarao, David J Beech

Research output: Contribution to journalArticle

196 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)69-72
Number of pages4
JournalNature
Volume451
Issue number7174
DOIs
Publication statusPublished - 3 Jan 2008

Keywords

  • Animals
  • Arthritis, Rheumatoid/metabolism
  • Cell Line
  • Disulfides/chemistry
  • Electric Conductivity
  • Humans
  • Oxidation-Reduction/drug effects
  • Patch-Clamp Techniques
  • Rabbits
  • TRPC Cation Channels/agonists
  • Thioredoxins/chemistry

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  • Cite this

    Xu, S-Z., Sukumar, P., Zeng, F., Li, J., Jairaman, A., English, A., Naylor, J., Ciurtin, C., Majeed, Y., Milligan, C. J., Bahnasi, Y. M., AlShawaf, E., Porter, K. E., Jiang, L-H., Emery, P., Sivaprasadarao, A., & Beech, D. J. (2008). TRPC channel activation by extracellular thioredoxin. Nature, 451(7174), 69-72. https://doi.org/10.1038/nature06414