TRPC6 is a stretch‐activated ion channel inhibited by tarantula toxin GsMTx‐4

Abstract

Tarantula toxins have been implicated as ion channels blockers of variety of ion channels. One of the tarantula venom compounds GsMTx-4, a 34 aminoacids peptide, has potentials to inhibit stretch activated non-selective cation channels and to block heart fibrillations. However the molecular nature of the targeted non-selective cation channels is not clear. Transient Receptor Potential (TRP) channels are mostly non-selective ion channels that have been implicated as mechano-sensors. The canonical subfamily of TRP channels (TRPC) are widely expressed in a variety of tissues including heart and vascular smooth muscle cells. TRPC6 have been suggested to be a mechano-sensitive channel in a number of review papers. However, direct evidence for stretch – activation of TRPC6 have not been reported. Here we report that TRPC6 is activated by hypo-osmolarity and direct membrane stretch. The stretch response had an activation threshold of about 75 mm of Hg. The stretch activation was not inhibited by the PLC inhibitor U73122, nor by actin polymerization inhibitor Cytochalasin D. However, both, the hypo-osmotic activation and the stretch response were inhibited by tarantula toxin GsMTx-4. These evidence support our hypothesis that members of TRPC family of ion channels are the molecular targets for the GsMTx-4 toxin. The data provide important information about the targeted proteins by tarantula toxin, that might promote it's future implications. Furthermore, here we identified a fundamental property of TRPC6 channel as a mechano-sensor, that likely defines its function in a number of tissues exposed to hydrostatic pressure, like vascular smooth muscle and glomerular podocytes.