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

This study inspects how LSD binds to the 5-HT2B (serotonin 2B) receptor (not the 2A receptor most commonly studied) to understand what signalling cascades it triggers. The researchers “determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states.” The information from this study can help with the design of novel psychedelics.

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.”

Authors: 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

Study details

Compounds studied
LSD

Topics studied
Neuroscience

Study characteristics
Bio/Neuro

Authors

Authors associated with this publication with profiles on Blossom

David E. Nichols
David E. Nichols is a researcher (specifically pharmacologist and medicinal chemist) at Purdue University (semi-retired in 2012). His psychedelics work has been ongoing since 1969.

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