Thermoring Basis for the Heat Inactivation in TRPV1

Transient receptor potential vanilloid-1 (TRPV1) in mammals exhibits the temperature-dependent inactivation in response to repeated or constant heat stimuli. However, the underlying structural factors or motifs are unresolved. In this computational study, the graph theory-based grid thermodynamic model was employed to reveal how the temperature-dependent non-covalent interactions as identified in the 3D structures of TRPV1 could develop a systemic fluidic grid-like mesh network with topological grids constrained as the thermo-rings to govern the heat inactivation from open and pre-open closed states in different temperature ranges. The results showed that the heat-evoked melting of three biggest grids in different gating states was responsible for the TRPV1 activity starting at 43°C and peaking at 56°C and ending at 61°C. While the second biggest grid controlled a reversible inactivation from the open state between56°C and 61°C, a smaller grid governed another irreversible inactivation from the pre-open closed state from 43°C to 61°C. Thus, two distinct inactivation pathways of TRPV1 may be involved in a protective mechanism in mammals against noxious heat.