It takes two vanilloid ligand bindings per channel to transduce painful capsaicin stimuli

The capsaicin receptor TRPV1 in mammals evolved the capability of integrating pain arising from combinations of noxious temperature or chemical irritants. Four-fold repetition of TRPV1 subunits makes an ion channel endowed with excellent sensitivity for pain detection, assisting this ionotropic receptor to differentiate graded injuries. We manipulated the stoichiometry and relative steric coordination of capsaicin binding at the molecular level, explicating rules with which a receptor codes pain within a broad range of intensity. The first ligand binding delivers small but clear initiation of channel activation. Maximal agonist action has already been reached in a receptor-in-tandem containing two or three wild-type receptor units, displaying activity comparable to the full liganded all-wild-type tandem tetramers. When the binding sites outnumbered ligands, independent action dominates in each channel. The non-vanilloid agonist 2-APB differs from capsaicin by adopting a distinct open mechanism since it does not demand a vanilloid group to activate. The sharing of the same pore greatly simplifies synergism to transduce relevant inputs by summation for pain signaling. And questions the need to explore deeper into other aspects of nociception.