Serine 3.39 and isoleucine 4.60 are key sites for 5‐HT2AR‐mediated Gs signaling

Certain amino acid sites of 5‐HT 2A R play crucial roles in interacting with various G proteins. Hallucinogens and non‐hallucinogens both act on 5‐HT 2A R but mediate different pharmacological effects, possibly due to the coupling of different G proteins. Therefore, this study identified the binding sites of hallucinogens and non‐hallucinogens with 5‐HT 2A R through molecular docking. We conducted site mutation to examine the impact of these sites on G proteins, in order to find out the sites that can distinguish the pharmacological effects of hallucinogens and non‐hallucinogens. Our results indicate that I4.60A and S3.39A did not affect the ability of hallucinogens to activate G q signaling, but significantly reduced G s signaling activation by hallucinogens. These results suggest that S3.39 and I4.60 are important for the activation of G s signaling by hallucinogens.