Abstract

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is a polymodal receptor that mediates the flux of cations across the membrane in response to several stimulus including heat, voltage and several ligands. The best known agonist of TRPV1 channels is capsaicin, the pungent component of "hot chilli peppers". Additionally, peptides obtained from the venom of poisonous animals binds to TRPV1 with high affinity to modulate channel gating. TRPV1 channels gating is also modulated by lipids such as PIP2, Lysophosphatidic acid and cholesterol. Here, we discuss the functional evidence regarding ligand-dependent activation of TRPV1 channels in the light of the structural data recently obtained by cryo-electron microscopy. Mechanistic insights on coupling between ligand binding and allosteric gating of TRPV1 channels and the relevance of an accurate biophysical characterization of polymodal receptors for drug design in novel pain therapies are also the focus of this review.