A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

TLDR

The TRP family of ion channels transduces diverse chemical and physical signals, and TRPC6 is a widely expressed receptor‑activated nonselective cation channel in vascular smooth muscle and other cells. This study demonstrates that TRPC6 also functions as a sensor of mechanically and osmotically induced membrane stretch. Pressure‑induced TRPC6 activation is PLC‑independent and is blocked by the tarantula peptide GsMTx‑4, which also inhibits receptor‑ or diacylglycerol‑mediated activation, suggesting a shared lipid‑sensing mechanism that likely regulates myogenic tone in vascular tissue.

Abstract

The TRP family of ion channels transduce an extensive range of chemical and physical signals. TRPC6 is a receptor-activated nonselective cation channel expressed widely in vascular smooth muscle and other cell types. We report here that TRPC6 is also a sensor of mechanically and osmotically induced membrane stretch. Pressure-induced activation of TRPC6 was independent of phospholipase C. The stretch responses were blocked by the tarantula peptide, GsMTx-4, known to specifically inhibit mechanosensitive channels by modifying the external lipid-channel boundary. The GsMTx-4 peptide also blocked the activation of TRPC6 channels by either receptor-induced PLC activation or by direct application of diacylglycerol. The effects of the peptide on both stretch- and diacylglycerol-mediated TRPC6 activation indicate that the mechanical and chemical lipid sensing by the channel has a common molecular mechanism that may involve lateral-lipid tension. The mechanosensing properties of TRPC6 channels highly expressed in smooth muscle cells are likely to play a key role in regulating myogenic tone in vascular tissue.