Molecular mechanism of TRPV2 channel modulation by cannabidiol

Ruth A. Pumroy; Amrita Samanta; Yuhang Liu; Taylor E.T. Hughes; Siyuan Zhao; Yevgen Yudin; Tibor Rohacs; Seungil Han; Vera Y. Moiseenkova-Bell

doi:10.7554/elife.48792

Molecular mechanism of TRPV2 channel modulation by cannabidiol

Ruth A. Pumroy, Amrita Samanta, Yuhang Liu, Taylor E.T. Hughes, Siyuan Zhao, Yevgen Yudin, Tibor Rohacs, Seungil Han, Vera Y. Moiseenkova-Bell

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

Transient receptor potential vanilloid (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV channel in apo and CBD-bound states in nanodiscs by cryoelectron microscopy. We show that CBD interacts with TRPV through a hydrophobic pocket located between S and S helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.

Original language	English (US)
Article number	e48792
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/elife.48792
State	Published - Sep 2019

All Science Journal Classification (ASJC) codes

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)

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10.7554/elife.48792

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@article{26351434be104fe2adbdcaaf937e04d3,

title = "Molecular mechanism of TRPV2 channel modulation by cannabidiol",

abstract = "Transient receptor potential vanilloid (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV channel in apo and CBD-bound states in nanodiscs by cryoelectron microscopy. We show that CBD interacts with TRPV through a hydrophobic pocket located between S and S helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.",

author = "Pumroy, {Ruth A.} and Amrita Samanta and Yuhang Liu and Hughes, {Taylor E.T.} and Siyuan Zhao and Yevgen Yudin and Tibor Rohacs and Seungil Han and Moiseenkova-Bell, {Vera Y.}",

note = "Funding Information: Acknowledgments We thank David Lodowski at Case Western Reserve University for help in the early stage of the project. We thank Sudha Chakrapani at Case Western Reserve University for assistance with MSP2N2 expression and purification. We thank Sabine Baxter for assistance with hybridoma and cell culture at the University of Pennsylvania Perelman School of Medicine Cell Center Services Facility. We acknowledge the use of instruments at the Electron Microscopy Resource Lab and at the Beckman Center for Cryo Electron Micrscopy at the University of Pennsylvania Perelman School of Medicine. We also thank Darrah Johnson-McDaniel for assistance with Krios microscope operation. This work was supported by grants from the National Institute of Health (R01GM103899 and R01GM129357 to V.Y.M.-B., R01NS055159 and R01GM093290 to T.R.). Publisher Copyright: {\textcopyright} Seungil Han.",

year = "2019",

month = sep,

doi = "10.7554/elife.48792",

language = "English (US)",

volume = "8",

journal = "eLife",

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publisher = "eLife Sciences Publications",

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T1 - Molecular mechanism of TRPV2 channel modulation by cannabidiol

AU - Pumroy, Ruth A.

AU - Samanta, Amrita

AU - Liu, Yuhang

AU - Hughes, Taylor E.T.

AU - Zhao, Siyuan

AU - Yudin, Yevgen

AU - Rohacs, Tibor

AU - Han, Seungil

AU - Moiseenkova-Bell, Vera Y.

N1 - Funding Information: Acknowledgments We thank David Lodowski at Case Western Reserve University for help in the early stage of the project. We thank Sudha Chakrapani at Case Western Reserve University for assistance with MSP2N2 expression and purification. We thank Sabine Baxter for assistance with hybridoma and cell culture at the University of Pennsylvania Perelman School of Medicine Cell Center Services Facility. We acknowledge the use of instruments at the Electron Microscopy Resource Lab and at the Beckman Center for Cryo Electron Micrscopy at the University of Pennsylvania Perelman School of Medicine. We also thank Darrah Johnson-McDaniel for assistance with Krios microscope operation. This work was supported by grants from the National Institute of Health (R01GM103899 and R01GM129357 to V.Y.M.-B., R01NS055159 and R01GM093290 to T.R.). Publisher Copyright: © Seungil Han.

PY - 2019/9

Y1 - 2019/9

N2 - Transient receptor potential vanilloid (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV channel in apo and CBD-bound states in nanodiscs by cryoelectron microscopy. We show that CBD interacts with TRPV through a hydrophobic pocket located between S and S helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.

AB - Transient receptor potential vanilloid (TRPV2) plays a critical role in neuronal development, cardiac function, immunity, and cancer. Cannabidiol (CBD), the non-psychotropic therapeutically active ingredient of Cannabis sativa, is an activator of TRPV and also modulates other transient receptor potential (TRP) channels. Here, we determined structures of the full-length rat TRPV channel in apo and CBD-bound states in nanodiscs by cryoelectron microscopy. We show that CBD interacts with TRPV through a hydrophobic pocket located between S and S helices of adjacent subunits, which differs from known ligand and lipid binding sites in other TRP channels. CBD-bound TRPV structures revealed that the S4-S5 linker plays a critical role in channel gating upon CBD binding. Additionally, nanodiscs permitted us to visualize two distinct TRPV apo states in a lipid environment. Together these results provide a foundation to further understand TRPV channel gating, their divergent physiological functions, and to accelerate structure-based drug design.

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Molecular mechanism of TRPV2 channel modulation by cannabidiol

Abstract

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