TRPV1 is a nonselective cation channel, member of the transient receptor potential (TRP) superfamily of ion channels. Predominantly expressed in sensory neurons and nociceptive fibers, TRPV1 is involved in important cellular functions, including heat-sensation, inflammation and pain.<br/>Activation of TRPV1 is triggered by a variety of stimuli, amongst which the binding of annular lipids, vanilloid ligands, and toxins, including the ultrapotent agonists resiniferatoxin (RTX) and the spider venom toxin (DkTx), acting from the extracellular milieu. We previously demonstrated that regulation of TRPV1 also relies on the behavior of nonpolar cavities, located between each S6 segment and the S4–S5 linker. We showed that hydration/dehydration of these cavities inversely correlates with hydration/dehydration of the pore lumen, ultimately affecting ion conduction. One question yet to be addressed about TRPV1 concerns its concerted activation by multiple stimuli, a process known as <i>polymodal activation</i>. Are multiple stimuli coupled to activate TRPV1? How do they synergistically act on the gate?<br/>To shed light on the intricate network of multiple interactions leading to TRPV1 activation, we combined molecular dynamics (MD) simulations, free energy (FE) calculations and computational docking; we confirmed that annular lipids, vanilloid ligands and toxins all play important roles in propagating the allosteric pathway leading to activation. First, we showed that, in activated channels, annular lipids adopt a peculiar ‘‘buried’’ conformation by concomitant binding of RTX and DkTx. Second, we showed that “buried” lipids simultaneously interact with RTX and with a side chain located on S6 in the proximity of the cavities subject to hydration/dehydration. Third, we demonstrated that formation of this quadripartite complex, - i.e. among toxin, vanilloid agonist, TRPV1 and lipids - is “bridged” by lipids, and is crucial to achieve gating motion, pore hydration and ion conduction. In summary, by elucidating the mechanisms by which multiple stimuli are transduced into gating motion, we revealed the principles governing TRPV1 polymodal activation and put the foundations to understanding, at the molecular level, the allosteric pathway governing its closed-to-open transition.

Allosteric modulation of the transient receptor potential vanilloid-1 (TRPV1) ion channel by lipids, toxins and small molecules ligands

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.