<p>The homotetrameric thermosensitive transient receptor potential vanilloid 1–4 (TRPV1-4) channels in sensory neurons are highly responsive to environmental heat stimuli. However, their primary heat sensors or triggers for heat activation have not been examined for cold activation. In this computational study, cold activation of minimal TRPV1 without the pore turret was compared with that of full-length human TRPV3. The former followed a pathway from the putative heat activation starter, while the latter tracked a different pathway starting far from the assumed heat activation point. The results showed that disrupting the highly conserved intersubunit interactions near the lower gate was necessary for final channel opening. Further, the former with the same starter shared temperature sensitivity with heat activation while the latter with the different triggers did not. Therefore, this mirrored thermosensitivity, together with the matched thresholds, can be used to confirm the location of the primary thermal sensor for TRPV1 or TRPV3, and further to define the primary thermal sensor of thermosensitive TRPV4 or TRPV2 once the same heat capacity mechanism is applied.</p>