Activation of TRPV1 by Lipids: Can Lipid Tails Bridge the Gap between the Vanilloid Binding Site and the Peripheral Cavities?

Abstract

The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel, member of the transient receptor potential superfamily of ion channels. TRPV1 is expressed in peripheral sensory neurons, where it transduces noxious stimuli into electrical signals, and is responsible for body temperature regulation, heat sensation, noxious and chronic pain. TRPV1 is activated by a variety of stimuli, including ligand binding at the vanilloid site. We previously discovered that rotation of a conserved residue on the S6 segment from the S4-S5 linker towards the pore is also implicated in TRPV1 activation. This movement is correlated with dehydration of peripheral cavities (PCs) located between S6 and the S4-S5 linker, and with hydration of the pore. However, the structural details for this mechanism remain to be elucidated. Here we explore the hypothesis that annular lipids mediate the allosteric coupling between the vanilloid site and the PCs, ultimately leading to TRPV1 activation. Our multi-microseconds molecular dynamics simulations and free energy calculations of several TRPV1 systems (i.e. TRPV1 bound to vanilloid ligands and/or to the spider venom toxin, Dk/Tx) revealed that annular lipids have a peculiar “buried” conformation upon concomitant binding of vanilloids and Dk/Tx. Interestingly, lipids in this conformation project the hydrophobic tails into the PCs, thereby triggering their dehydration and the consequent opening of the channel. In conclusion, our results elucidate the molecular underpinnings of TRPV1 allosteric regulation by annular lipids, and sheds light on the mechanism by which the binding of vanilloid ligands is coupled to gating motion.