Heat-dependent opening of TRPV1 in the presence of capsaicin

Multiple cryo-EM structures of rat TRPV1 at different temperatures illustrate steps in the heat-dependent gating of this important sensory receptor. Transient receptor potential vanilloid member 1 (TRPV1) is a Ca2+-permeable cation channel that serves as the primary heat and capsaicin sensor in humans. Using cryo-EM, we have determined the structures of apo and capsaicin-bound full-length rat TRPV1 reconstituted into lipid nanodiscs over a range of temperatures. This has allowed us to visualize the noxious heat-induced opening of TRPV1 in the presence of capsaicin. Notably, noxious heat-dependent TRPV1 opening comprises stepwise conformational transitions. Global conformational changes across multiple subdomains of TRPV1 are followed by the rearrangement of the outer pore, leading to gate opening. Solvent-accessible surface area analyses and functional studies suggest that a subset of residues form an interaction network that is directly involved in heat sensing. Our study provides a glimpse of the molecular principles underlying noxious physical and chemical stimuli sensing by TRPV1, which can be extended to other thermal sensing ion channels.

Automated summary

The cryo-EM structures of rat TRPV1 at different temperatures reveal the heat-dependent gating mechanism of this sensory receptor. By visualizing the opening of TRPV1 in response to noxious heat in the presence of capsaicin, the study shows that the conformational transitions leading to TRPV1 opening occur stepwise. The research also suggests that a subset of residues forms an interaction network directly involved in heat sensing, providing insights into the molecular principles underlying sensing of physical and chemical stimuli by TRPV1, which may be applicable to other thermal sensing ion channels.