Tyrosine residue in the TRPV1 vanilloid binding pocket regulates deactivation kinetics

Rakesh Kumar, Adina Hazan, Arijit Basu, Nomi Zalcman, Henry Matzner, Avi Priel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Vanilloids are pain evoking molecules that serve as ligands of the "heat and capsaicin receptor" TRPV1. Binding of either endogenous or exogenous vanilloids evokes channel and subsequent neuronal activation, leading to pain sensation. Despite its pivotal physiological role, the molecular basis of TRPV1 activation and deactivation is not fully understood. The highly conserved tyrosine in position 511 (Tyr511) of the rat TRPV1 (rTRPV1) was the first residue to be identified as a necessary participant in the vanilloid-mediated response. rTRPV1 cryo-EM structures implicated rotation of this residue in the vanilloids bound state. Therefore, we hypothesize that the rTRPV1 Tyr511 residue entraps vanilloids in their binding site, prolonging channel activity. To test our hypothesis, we generated an array of rTRPV1 mutants, containing the whole spectrum of Tyr511 substitutions, and tested their response to both exo- and endovanilloids. Our data show that only substitutions of Tyr511 to aromatic amino acids were able to mimic, albeit partially, the vanilloid-evoked activation pattern of the wt receptor. Although these substitutions reduced the channel sensitivity to vanilloids, a maximal open-channel lifetime could be achieved. Moreover, whereas their current activation rate remains intact, receptors with Tyr511 substitutions exhibited a faster current deactivation. Our findings therefore suggest that the duration of channel activity evoked by vanilloids is regulated by the interaction between Tyr511 and the agonist. To conclude, we suggest that Tyr511-mediated anchoring of vanilloids in their binding pocket is pivotal for TRPV1 activation and subsequent pain sensation.

Original languageAmerican English
Pages (from-to)13855-13863
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number26
DOIs
StatePublished - 24 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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