Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Can Cao; Ximena Barros-Álvarez; Shicheng Zhang; Kuglae Kim; Marc A. Dämgen; Ouliana Panova; Carl Mikael Suomivuori; Jonathan F. Fay; Xiaofang Zhong; Brian E. Krumm; Ryan H. Gumpper; Alpay B. Seven; Michael J. Robertson; Nevan J. Krogan; Ruth Hüttenhain; David E. Nichols; Ron O. Dror; Georgios Skiniotis; Bryan L. Roth

doi:10.1016/j.neuron.2022.08.006

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Can Cao
, Ximena Barros-Álvarez
, Shicheng Zhang
, Kuglae Kim
, Marc A. Dämgen
, Ouliana Panova
, Carl Mikael Suomivuori
, Jonathan F. Fay
, Xiaofang Zhong
, Brian E. Krumm
, Ryan H. Gumpper
, Alpay B. Seven
, Michael J. Robertson
, Nevan J. Krogan
, Ruth Hüttenhain
, David E. Nichols
, Ron O. Dror
, Georgios Skiniotis
, Bryan L. Roth

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

126 Scopus citations

Abstract

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT_2A serotonin receptor (HTR2A), the 5-HT_2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

Original language	English
Pages (from-to)	3154-3167.e7
Journal	Neuron
Volume	110
Issue number	19
DOIs	https://doi.org/10.1016/j.neuron.2022.08.006
State	Published - 5 Oct 2022
Externally published	Yes

Keywords

Gq protein
HTR2B
LSD
functional selectivity
psychedelic
signaling transduction
structural biology
β-arrestin-1

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10.1016/j.neuron.2022.08.006

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Cao, C., Barros-Álvarez, X., Zhang, S., Kim, K., Dämgen, M. A., Panova, O., Suomivuori, C. M., Fay, J. F., Zhong, X., Krumm, B. E., Gumpper, R. H., Seven, A. B., Robertson, M. J., Krogan, N. J., Hüttenhain, R., Nichols, D. E., Dror, R. O., Skiniotis, G., & Roth, B. L. (2022). Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Neuron, 110(19), 3154-3167.e7. https://doi.org/10.1016/j.neuron.2022.08.006

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title = "Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD",

abstract = "Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.",

keywords = "Gq protein, HTR2B, LSD, functional selectivity, psychedelic, signaling transduction, structural biology, β-arrestin-1",

author = "Can Cao and Ximena Barros-{\'A}lvarez and Shicheng Zhang and Kuglae Kim and D{\"a}mgen, \{Marc A.\} and Ouliana Panova and Suomivuori, \{Carl Mikael\} and Fay, \{Jonathan F.\} and Xiaofang Zhong and Krumm, \{Brian E.\} and Gumpper, \{Ryan H.\} and Seven, \{Alpay B.\} and Robertson, \{Michael J.\} and Krogan, \{Nevan J.\} and Ruth H{\"u}ttenhain and Nichols, \{David E.\} and Dror, \{Ron O.\} and Georgios Skiniotis and Roth, \{Bryan L.\}",

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year = "2022",

month = oct,

day = "5",

doi = "10.1016/j.neuron.2022.08.006",

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Cao, C, Barros-Álvarez, X, Zhang, S, Kim, K, Dämgen, MA, Panova, O, Suomivuori, CM, Fay, JF, Zhong, X, Krumm, BE, Gumpper, RH, Seven, AB, Robertson, MJ, Krogan, NJ, Hüttenhain, R, Nichols, DE, Dror, RO, Skiniotis, G & Roth, BL 2022, 'Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD', Neuron, vol. 110, no. 19, pp. 3154-3167.e7. https://doi.org/10.1016/j.neuron.2022.08.006

TY - JOUR

T1 - Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

AU - Cao, Can

AU - Barros-Álvarez, Ximena

AU - Zhang, Shicheng

AU - Kim, Kuglae

AU - Dämgen, Marc A.

AU - Panova, Ouliana

AU - Suomivuori, Carl Mikael

AU - Fay, Jonathan F.

AU - Zhong, Xiaofang

AU - Krumm, Brian E.

AU - Gumpper, Ryan H.

AU - Seven, Alpay B.

AU - Robertson, Michael J.

AU - Krogan, Nevan J.

AU - Hüttenhain, Ruth

AU - Nichols, David E.

AU - Dror, Ron O.

AU - Skiniotis, Georgios

AU - Roth, Bryan L.

PY - 2022/10/5

Y1 - 2022/10/5

N2 - Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

AB - Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT2A serotonin receptor (HTR2A), the 5-HT2B serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

KW - Gq protein

KW - HTR2B

KW - LSD

KW - functional selectivity

KW - psychedelic

KW - signaling transduction

KW - structural biology

KW - β-arrestin-1

UR - https://www.scopus.com/pages/publications/85139008292

U2 - 10.1016/j.neuron.2022.08.006

DO - 10.1016/j.neuron.2022.08.006

M3 - Article

C2 - 36087581

AN - SCOPUS:85139008292

SN - 0896-6273

VL - 110

SP - 3154-3167.e7

JO - Neuron

JF - Neuron

IS - 19

ER -

Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD

Abstract

Keywords

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