TRPV1 pore turret dictates distinct DkTx and capsaicin gating

The TRPV1 channel integrates noxious stimuli from multiple sources to evoke an appropriate pain response. However, while different stimuli evoke distinct channel activation, the underlying molecular mechanisms remain unclear. Here, we aim at elucidating the structural determinants that regulate the different TRPV1 responses to two toxins: capsaicin and double-knot toxin (DkTx). We found that the channel pore turret domain imposes two opposite effects on the responses to these toxins. While it restricts the ion conductance of the DkTx-evoked current, it stabilizes the open channel state evoked by capsaicin. Together, our results indicate that TRPV1 pore turret dictates different gating mechanisms in response to agonists acting through different binding domains.