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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural biology study Peer reviewed |
|---|---|
| Topics | LSD Serotonin |
| Keywords | Gq protein Htr2b Functional selectivity Signaling transduction Structural biology Β-arrestin-1 Psychedelics hallucinogens Entheogens Protein structure Receptor binding Neuroscience neurotransmitters Brain chemistry Serotonin receptors |
| Citations | 158 |
| Key points | 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.