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PMID: 24305161 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

TRPV1 structures in distinct conformations reveal activation mechanisms.

Nature ·Vol. 504 ·No. 7478 ·2013-12-05 ·Pages 113-8

Cao E, Liao M, Cheng Y, Julius D

Abstract

Transient receptor potential (TRP) channels are polymodal signal detectors that respond to a wide range of physical and chemical stimuli. Elucidating how these channels integrate and convert physiological signals into channel opening is essential to understanding how they regulate cell excitability under normal and pathophysiological conditions. Here we exploit pharmacological probes (a peptide toxin and small vanilloid agonists) to determine structures of two activated states of the capsaicin receptor, TRPV1. A domain (consisting of transmembrane segments 1-4) that moves during activation of voltage-gated channels remains stationary in TRPV1, highlighting differences in gating mechanisms for these structurally related channel superfamilies. TRPV1 opening is associated with major structural rearrangements in the outer pore, including the pore helix and selectivity filter, as well as pronounced dilation of a hydrophobic constriction at the lower gate, suggesting a dual gating mechanism. Allosteric coupling between upper and lower gates may account for rich physiological modulation exhibited by TRPV1 and other TRP channels.

MeSH Terms
Animals Models, Molecular Mutation Protein Structure, Tertiary Rats TRPV Cation Channels/chemistry,genetics,physiology
Chemicals
TRPV Cation Channels Trpv1 protein, rat
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cao Erhu
1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2].
Liao Maofu
Cheng Yifan
Julius David
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature12823
Published
2013-12-05
Pages
113-8
Language
English
Region
England
NLM ID
0410462
PMCID
PMC4023639
Subset
IM
Grants
NINDS NIH HHS · R01NS047723 · United States
NINDS NIH HHS · R01 NS047723 · United States
NINDS NIH HHS · R01 NS065071 · United States
NINDS NIH HHS · R01NS065071 · United States
NIGMS NIH HHS · R01 GM098672 · United States
NCRR NIH HHS · S10RR026814 · United States
NIGMS NIH HHS · R01GM098672 · United States
NCRR NIH HHS · S10 RR026814 · United States
Databases
PDB
3J5Q, 3J5R
Corrections
CommentIn
PMID: 24305155
CommentIn
PMID: 27000851
External Links
PubMed source DOI: 10.1038/nature12823 PMC Full Text View journal details
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