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Kasimova MA , Yazici AT , Yudin Y , Granata D , Klein ML , Rohacs T , Carnevale V
A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine
J Gen Physiol. 2018 Nov 5;150(11) :1554-1566
PMID: 30333107    PMCID: PMC6219692    URL: https://www.ncbi.nlm.nih.gov/pubmed/30333107
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The transient receptor potential channel vanilloid type 1 (TRPV1) is activated by a variety of endogenous and exogenous stimuli and is involved in nociception and body temperature regulation. Although the structure of TRPV1 has been experimentally determined in both the closed and open states, very little is known about its activation mechanism. In particular, the conformational changes that occur in the pore domain and result in ionic conduction have not yet been identified. Here we suggest a hypothetical molecular mechanism for TRPV1 activation, which involves rotation of a conserved asparagine in S6 from a position facing the S4-S5 linker toward the pore. This rotation is associated with hydration of the pore and dehydration of the four peripheral cavities located between each S6 and S4-S5 linker. In light of our hypothesis, we perform bioinformatics analyses of TRP and other evolutionary related ion channels, evaluate newly available structures, and reexamine previously reported water accessibility and mutagenesis experiments. These analyses provide several independent lines of evidence to support our hypothesis. Finally, we show that our proposed molecular mechanism is compatible with the prevailing theory that the selectivity filter acts as a secondary gate in TRPV1.
1540-7748 Kasimova, Marina A Orcid: 0000-0002-7497-9448 Yazici, Aysenur Torun Yudin, Yevgen Granata, Daniele Klein, Michael L Rohacs, Tibor Orcid: 0000-0003-3580-2575 Carnevale, Vincenzo Orcid: 0000-0002-1918-8280 P01 GM055876/GM/NIGMS NIH HHS/United States R01 GM093290/GM/NIGMS NIH HHS/United States R01 NS055159/NS/NINDS NIH HHS/United States S10 OD020095/OD/NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. United States J Gen Physiol. 2018 Nov 5;150(11):1554-1566. doi: 10.1085/jgp.201812124. Epub 2018 Oct 17.