TRPV1 and Heat Perception
TRPV1 is a non-selective cation channel expressed on sensory neurons of the dorsal root and trigeminal ganglia. It acts as a polymodal sensor, responding to temperatures above ~43 °C, acid (pH < 6), and vanilloid compounds including capsaicin. When activated, it opens and allows calcium ions to flood into the cell, generating an action potential the brain interprets as burning pain.
Capsaicin Binding Site
Capsaicin binds to a hydrophobic pocket in TRPV1's transmembrane domain — specifically at the S4–S5 linker and portions of S2–S4. Cryo-EM structures show the vanillyl head group hydrogen-bonding to Thr550 and Ser512, while the acyl tail inserts into a hydrophobic groove. Binding shifts the channel's temperature activation threshold from ~43 °C to room temperature, holding it constitutively open.
Desensitization and Tachyphylaxis
Prolonged TRPV1 activation leads to calcium-dependent desensitization — the channel closes despite continued ligand presence. This is why repeated capsaicin exposure temporarily reduces heat sensitivity (tachyphylaxis). At very high doses, TRPV1-expressing neurons may undergo defunctionalization, the basis of capsaicin's clinical use as a topical analgesic for neuropathic pain.