Signaling mechanisms of the prototypical psychedelic LSD

Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2-family receptors are the key targets of the prototypical psychedelic LSD. Although the canonical signaling pathway for 5-HT2 receptors is mediated by Gq protein, recent studies suggest that G-protein independent signaling, namely β-arrestin signaling pathway, may be also essential for actions of LSD in vitro and in vivo. To gain comprehensive molecular insights into the signaling mechanisms of LSD, we determined the cryoEM structures of LSD-bound 5-HT2BR in transducer-free state, G protein-coupled state and β-arrestin-1-coupled state, respectively. Besides, we use mass spectrometry to determine the phosphorylation sites of LSD-bound 5-HT2BR.