Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD.
Neuron – October 05, 2022
Source: PubMed
Summary
LSD's remarkable ability to alter consciousness stems from its precise dance with brain receptors. Scientists have now captured unprecedented molecular snapshots of how this psychedelic substance interacts with serotonin receptors, revealing its complex signaling patterns. Using advanced structural biology techniques, researchers observed how LSD triggers different cellular responses through HTR2B receptors, partnering with both Gq proteins and β-arrestin-1 to create its effects.
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.