Temperature-responsive contacts in TRPV1 concentrate in the cytoplasmic coupling domains

TRPV1, the heat-activated cation channel of pain-sensing neurons, holds the potential to become a major target for new analgesics. However, its mechanism of heat detection remains elusive. Researchers set out to uncover the exact location of the temperature-responsive contact network within TRPV1. To do so, they simulated the channel in a multicomponent membrane at six temperatures ranging from its activation threshold to three different salt concentrations.

By breaking down the recurring contacts across the four identical subunits into collective thermal modes, the researchers tested each mode against temperature and, for comparison, salinity.

Results indicated that only one dominant atomistic mode aligns with temperature changes, accounting for 59% of the mode's variance. Surprisingly, no mode correlates with salinity at either resolution. The temperature-responsive mode predominantly concentrates in the cytoplasmic domains, comprising 80% of its variance, compared to 63% of all contact variance.

This mode shows the most enrichment in the linker domain, which connects the ankyrin repeats to the transmembrane domain. Upon heating, the linker releases the C-terminal domain and increases its binding affinity to the ankyrin repeats. Lipid contacts cluster around the transmembrane and TRP domains, with the majority of those reaching the ankyrin repeats and linker residing with the anionic inner-leaflet phosphatidylserine.

Although the coarse-grained model successfully replicated atomistic fluctuations and lipid organization, it only revealed the temperature mode at the atomistic resolution. The localization of this thermally-responsive mode aligns with that of the dominant temperature mode in a closely related channel, TRPV3. These findings provide valuable insights into the search for the heat sensor within TRPV1 and TRPV3.

It is now apparent that the contact network responds to temperature changes not in the pore, but in the cytoplasmic coupling region where the ankyrin repeats, the linker, and the C-terminal domain intersect.