The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel

Fan Yang (), Xian Xiao, Bo Hyun Lee, Simon Vu, Wei Yang, Vladimir Yarov-Yarovoy and Jie Zheng ()
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Fan Yang: Zhejiang University School of Medicine
Xian Xiao: University of California
Bo Hyun Lee: University of California
Simon Vu: University of California
Wei Yang: Zhejiang University School of Medicine
Vladimir Yarov-Yarovoy: University of California
Jie Zheng: University of California

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Φ-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4–S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

Date: 2018
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DOI: 10.1038/s41467-018-05339-6

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