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
Neuron October 5, 2022 DOI: 10.1016/j.neuron.2022.08.006 via PubMed
Summary
AI-generated from the abstractLysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.
Study at a glance
| Characteristics | Structural biology study Peer reviewed |
|---|---|
| Topics | LSD |
| Keywords | Gq protein Htr2b Functional selectivity Signaling transduction |
| Citations | 158 |
| Key finding | Cryo-EM structures of LSD-bound 5-HT2B receptor in transducer-free, Gq-coupled, and β-arrestin-1-coupled states reveal distinct signaling snapshots from partially to fully active states. |
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.