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

Neuron. 2022 Oct 5;110(19):3154-3167.e7. doi: 10.1016/j.neuron.2022.08.006. Epub 2022 Sep 9.

Authors

Can Cao¹, Ximena Barros-Álvarez², Shicheng Zhang¹, Kuglae Kim¹, Marc A Dämgen³, Ouliana Panova², Carl-Mikael Suomivuori³, Jonathan F Fay⁴, Xiaofang Zhong⁵, Brian E Krumm¹, Ryan H Gumpper¹, Alpay B Seven², Michael J Robertson², Nevan J Krogan⁵, Ruth Hüttenhain⁵, David E Nichols⁶, Ron O Dror⁷, Georgios Skiniotis⁸, Bryan L Roth⁹

Affiliations

¹ Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599-7365, USA.
² Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA.
³ Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 7599-7365, USA.
⁵ Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA, USA; J. David Gladstone Institutes, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
⁶ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
⁷ Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: ron.dror@stanford.edu.
⁸ Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: yiorgo@stanford.edu.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599-7365, USA; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7365, USA. Electronic address: bryan_roth@med.unc.edu.

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.

Keywords: Gq protein; HTR2B; LSD; functional selectivity; psychedelic; signaling transduction; structural biology; β-arrestin-1.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Hallucinogens* / metabolism
Hallucinogens* / pharmacology
Lysergic Acid Diethylamide* / chemistry
Lysergic Acid Diethylamide* / metabolism
Lysergic Acid Diethylamide* / pharmacology
Receptors, Serotonin
Serotonin
beta-Arrestins / metabolism

Substances

Hallucinogens
Receptors, Serotonin
beta-Arrestins
Serotonin
Lysergic Acid Diethylamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding