1. Institute of Membrane and Systems Biology, Garstang Building, Faculty of Biological Sciences, and,
2. School of Medicine, University of Leeds, Leeds LS2 9JT, UK
3. Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds LS7 4SA, UK
4. These authors contributed equally to this work.
5. Present address: Postgraduate Medical Institute & Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, UK.

Correspondence to: David J. Beech¹ Correspondence and requests for materials should be addressed to D.J.B. (Email: d.j.beech@leeds.ac.uk).

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^{1, 2}. 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^{3, 4, 5} 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^{6, 7, 8, 9}. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis^{8, 10, 11, 12}, an inflammatory joint disease that disables millions of people worldwide¹³. 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.

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