Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD
Barros-Álvarez, X., Cao, C., Dämgen, M. A., Dror, R. O., Fay, J. F., Gumpper, R. H., Hüttenhain, R., Kim, K., Krogan, N. J., Krumm, B. E., Nichols, D. E., Panova, O., Robertson, M. J., Roth, B. L., Seven, A. B., Skiniotis, G., Suomivuori, C-M., Zhong, X.
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.