A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation

TRPV1 is a polymodal receptor ion channel that is best known to function as a molecular thermometer. It is activated in diverse ways, including by heat, protons (low pH), and vanilloid compounds, such as capsaicin. In this review, we summarize molecular studies of TRPV1 thermosensing, focusing on the cross-talk between heat and other activation modes. Additional insights from TRPV1 isoforms and non-rodent/non-human TRPV1 ortholog studies are also discussed in this context. While the molecular mechanism of heat activation is still emerging, it is clear that TRPV1 thermosensing is modulated allosterically, i.e., at a distance, with contributions from many distinct regions of the channel. Similarly, current studies identify cross-talk between heat and other TRPV1 activation modes, such as protons and capsaicin, and that these modes can generally be selectively disentangled. In aggregate, this suggests that future TRPV1 molecular studies should define allosteric pathways and provide mechanistic insight, thereby enabling mode-selective manipulation of the polymodal receptor. These advances are anticipated to have significant implications in both basic and applied biomedical sciences.