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

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

doi:10.1016/j.neuron.2022.08.006

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

Journal Article · Fri Sep 09 00:00:00 EDT 2022 · Neuron

DOI:https://doi.org/10.1016/j.neuron.2022.08.006· OSTI ID:2424034

Cao, Can ^[1]; Barros-Álvarez, Ximena ^[2]; Zhang, Shicheng ^[1]; Kim, Kuglae ^[3]; Dämgen, Marc A. ^[2]; Panova, Ouliana ^[2]; Suomivuori, Carl-Mikael ^[2]; Fay, Jonathan F. ^[1]; Zhong, Xiaofang ^[4]; Krumm, Brian E. ^[1]; Gumpper, Ryan H. ^[1]; Seven, Alpay B. ^[2]; Robertson, Michael J. ^[2]; Krogan, Nevan J. ^[4]; Hüttenhain, Ruth ^[4]; Nichols, David E. ^[1]; Dror, Ron O. ^[2]; Skiniotis, Georgios ^[2]; Roth, Bryan L. ^[1]

University of North Carolina, Chapel Hill, NC (United States)
Stanford Univ., CA (United States)
University of North Carolina, Chapel Hill, NC (United States); Yonsei Univ. (Korea, Republic of)
Univ. of California, San Francisco, CA (United States); J. David Gladstone Institutes, San Francisco, CA (United States)

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. Here, 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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2424034

Journal Information:: Neuron, Journal Name: Neuron Journal Issue: 19 Vol. 110; ISSN 0896-6273

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Gq protein
HTR2B
LSD
functional selectivity
psychedelic
signaling transduction
structural biology
β-arrestin-1

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

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