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TRPC1 forms the stretch-activated cation channel in vertebrate cells


The mechanosensitive cation channel (MscCa) transduces membrane stretch into cation (Na+, K+, Ca2+ and Mg2+) flux across the cell membrane, and is implicated in cell-volume regulation1, cell locomotion2, muscle dystrophy3 and cardiac arrhythmias4. However, the membrane protein(s) that form the MscCa in vertebrates remain unknown. Here, we use an identification strategy that is based on detergent solubilization of frog oocyte membrane proteins, followed by liposome reconstitution and evaluation by patch-clamp5. The oocyte was chosen because it expresses the prototypical MscCa (≥107MscCa/oocyte)6 that is preserved in cytoskeleton-deficient membrane vesicles7. We identified a membrane-protein fraction that reconstituted high MscCa activity and showed an abundance of a protein that had a relative molecular mass of 80,000 (Mr 80K). This protein was identified, by immunological techniques, as the canonical transient receptor potential channel 1 (TRPC1)8,9,10. Heterologous expression of the human TRPC1 resulted in a >1,000% increase in MscCa patch density, whereas injection of a TRPC1-specific antisense RNA abolished endogenous MscCa activity. Transfection of human TRPC1 into CHO-K1 cells also significantly increased MscCa expression. These observations indicate that TRPC1 is a component of the vertebrate MscCa, which is gated by tension developed in the lipid bilayer, as is the case in various prokaryotic mechanosensitive (Ms) channels11.

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We thank C. Montell for the cDNA, T. Jespersen for the pXOOM vector, A. Rodgers, C. Thompson (UWA) and B. Xu (UTMB) for help with the FPLC; L. Vergara for help with the imaging; D. Roberts for collecting the Litoria; and D. Konkel for comments on the manuscript. We also thank the Cystic Fibrosis Foundation, the Department of Defense and the Raine Medical Research Foundation for their support.

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The authors declare no competing financial interests.

Correspondence to Owen P. Hamill.

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Figure 1: Mechanosensitive channel (MscCa) activity is preserved after protein detergent solubilization and liposome reconstitution of frog oocyte membrane.
Figure 2: Stretch-activated multi-channel and single-channel currents measured in cell-attached patches from control (a, b) and human TRPC1-expressing (c,d) oocytes at different patch potentials.
Figure 3: Mechanosensitive channel (MscCa) activity in control and human TRPC1 mRNA-injected oocytes and the effects of human TRPC antisense RNA on native MscCa activity.
Figure 4: Transfection of CHO-K1 cells with human TRPC1 results in increased mechanosensitive channel (MscCa) activity.