Mechanism Of Trpv1 Activation By Oxytocin

TRPV1 is an ion channel responsible for transducing noxious stimuli, such as high temperatures, in the peripheral nervous system. The conformational transition between closed and open states have been recently explored computationally; hydration of the pore and thus ion permeation relies on the motion of a polar side-chain. However, it is not fully understood yet how this side-chain motion can be triggered by ligands binding to the extracellular side of the channel. Here, we show that oxytocin affects the channel opening by binding to a set of potentially evolutionary conserved and deeply annular lipids. In particular, two conformations are possible for the annular lipids: an “up” conformation observed in the apo structure and a “down” configuration favored by the binding of oxytocin. Only in the “down” conformation, the annular lipid projects its hydrophobic tail into the interface between S6 and the S4-S5 linker, thereby promoting the rotation of N676 and thus activation of the channel.