TRPC channel activation by extracellular thioredoxin

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Abstract
Reducing agents can activate different members of the transient receptor potential (TRP) superfamily of ion channels (TRPC1 and TRPC5) by breaking a disulphide bridge in the extracellular loop adjacent to the ion permation pore. A high concentration of the endogenous reducing agent, thioredoxin, is present in rheumatoid arthritis and may reduce secretion of matrix metalloproteinases by its inhibition of TRPC1 and TRPC5. 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 factor1,2. 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 channels3,4,5 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 unknown6,7,8,9. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis8,10,11,12, 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.