Temperature-responsive contacts in TRPV1 concentrate in the cytoplasmic coupling domains
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TRPV1, the heat-activated cation channel of pain-sensing neurons, is a major target for new analgesics, yet where it senses heat remains unresolved. Candidate sensors have been proposed in nearly every part of its structure, from the ankyrin repeats to the pore. Here we ask where the contact network of the closed channel responds to temperature. We simulated human TRPV1 in a multicomponent membrane at six temperatures spanning its activation threshold and three salt concentrations, at atomistic and coarse-grained resolution. We decomposed the contacts that recur across its four identical subunits into collective thermal modes and tested each mode against temperature and, as a control, salinity. Only the leading atomistic mode follows temperature, which explains 59% of its variance and no mode follows salinity at either resolution. The temperature mode places 80% of its variance in the cytoplasmic domains, against 63% of all contact variance, and is most enriched in the linker domain that joins the ankyrin repeats to the transmembrane domain. On heating, the linker releases the C-terminal domain and binds the ankyrin repeats more tightly. Lipid contacts cluster along the transmembrane and TRP domains, and the few that reach the ankyrin repeats and the linker are mostly with the anionic inner-leaflet phosphatidylserine. The coarse-grained model reproduces the atomistic fluctuations and lipid organization, but the temperature mode emerges only at atomistic resolution. Its localization matches that of the dominant temperature mode of the related channel TRPV3. These results narrow the search for the heat sensor. In both channels, the contact network responds to temperature not in the pore but in the cytoplasmic coupling region where the ankyrin repeats, the linker, and the C-terminal domain meet.
Author summary
Our sense of burning heat starts with an ion channel, TRPV1, that opens when tissue warms past about 42 degrees Celsius. Where in this large protein heat is detected is still debated. Experiments have implicated almost every region. We used computer simulations to follow the contacts between the channel’s amino acids at six temperatures and three salt concentrations, at two levels of detail. Because each simulation can get stuck in one arrangement, we treated the channel’s four identical subunits as a built-in check and kept only contacts that formed in at least two of them. What remained showed one clear pattern that tracks temperature and none that tracks salt. The pattern sits not in the pore but below the membrane, where the ankyrin repeats, a linker segment, and the tail of the protein meet. As the temperature rises, the linker lets go of the tail and holds the ankyrin repeats more tightly. A simpler, faster model of the channel did not reproduce this pattern. Our results point to specific contacts, between the linker and the tail, that experiments can now test.
