The transient receptor potential vanilloid receptor 1 (TRPV1) is a nonselective cation channel expressed in peripheral sensory neurons to transduce noxious stimuli into electrical signals. Activation of TRPV1 is triggered by a variety of stimuli, including noxious heat and the binding of phosphoinositide lipids, vanilloid ligands (i.e. capsaicin, the active component of chili peppers or its agonist resininferatoxin, RTX) and the spider venom toxin Dk/Tx, acting from the extracellular milieu. Interestingly, all these lipids and ligands participate in the formation of biomolecular complexes with TRPV1, either in the apo (bound to phosphoinositides) or activated (bound to RTX, Dk/Tx and annular lipids) channels, as shown by recent Cryo-EM experiments. Despite the availability of structural data, the mechanistic aspects of TRPV1 modulation by multiple stimuli and, importantly, the many roles played by lipids in the activation of this channel, are yet to be elucidated. How phosphoinositide lipids regulate TRPV1, and what’s the nature of the phosphoinositide bound at the vanilloid site in the apo TRPV1? How are vanilloid ligands in the open TRPV1 coupled to external stimuli to synergistically act on the gate? Is this coupling mediated by lipids?<br/>To address the above questions we used extensive molecular dynamics simulations and free energy calculations of a number of TRPV1/lipid structures in complex with different biomolecular ligands (i.e. vanilloid agonists, but also antagonists, in the presence or absence of Dk/Tx). First, by combining experimental and computational studies, we demonstrated that the lipid bound at the vanilloid binding site of apo TRPV1 is phosphatidylinositol. Then, we showed by computation that annular lipids are permanently bound to and stabilize TRPV1 in the open state. While lipid head-groups interact with Dk/Tx, the tails are simultaneously in contact with RTX and with a side chain crucial for the movement of the S4-S5 linker. These results shed light on the mechanism by which vanilloid binding is transduced into gating motion, and rationalize the experimentally observed allosteric coupling between Dk/Tx and RTX.

On the many roles played by lipids in the activation TRPV1, the noxious heat and capsaicin receptor

2019 Fall National Meeting

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