Opening TRPP2 ( PKD2L1 ) requires the transfer of gating charges

Significance Dysfunction of polycystin TRP channels (TRPPs) is associated with polycystic kidney disease (PKD), but their biophysical and structural regulation is poorly understood. We report that TRPP2 voltage sensor activation is required to open the conducting pore, regardless of polymodal stimuli. Each of the 4 voltage sensor domains delivers at least 1 gating charge prior to TRPP2 channel opening while forming state-dependent cation–π interactions. Since these interacting positions are conserved among voltage-gated ion channels, we propose that this canonical gating mechanism was preserved during TRPP2 evolution. Our results provide a structural framework for understanding the regulation of TRPP2 in cilia and plasma membranes.