Pathway-selective Gi1, but not Gq, protein activation distinguishes hallucinogenic from non-hallucinogenic serotonin 5-HT2A receptor agonists in the human cortex.
Patricia Miranda-Azpiazu, Rebeca Diez-Alarcia, Itziar Muneta-Arrate, Aintzane García-Bea, Rafaël Maldonado, Benito Morentin, Javier González-Maeso, J Javier Meana
Neurochemistry International November 6, 2026 DOI: 10.1016/j.neuint.2026.106285 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacology study using post-mortem human brain tissue and knockout mouse tissue Peer reviewed |
|---|---|
| Population | Post-mortem human prefrontal cortex tissue and 5-HT2A receptor knockout mouse brain tissue |
| Interventions | (±)DOI TCB-2 LSD Ariadne 2-Br-LSD lisuride NEM |
| Measures | [35S]GTPγS binding assays coupled with antibody immunoprecipitation against different Gα protein subtypes |
| Topics | Serotonin |
| Keywords | G protein Biased agonism Functional selectivity Hallucinogens Human brain Psychedelics |
| Key points | Hallucinogenic 5-HT2A agonists (±)DOI, TCB-2, and LSD activated both Gq/11 and Gi1 proteins through 5-HT2A receptors, while non-hallucinogenic agonists Ariadne, 2-Br-LSD, and lisuride activated Gq/11 but not Gi1. The authors propose that Gi1 protein recruitment in human brain may be associated with the psychedelic properties of 5-HT2A agonists and suggest functional selectivity in receptor-G protein coupling. |
Abstract
The serotonin 5-HT2A receptor (5-HT2AR) signaling involves canonical Gq/11 proteins and alternative pathways, such as recruitment of other G proteins. It has been proposed that the 5-HT2AR-mediated activation of inhibitory Gi/o proteins accounts for the hallucinogenic properties of psychedelics. Here, the differential signaling patterns between hallucinogenic and non-hallucinogenic 5-HT2AR agonists were evaluated in post-mortem human prefrontal cortex using [35S]GTPγS binding assays coupled with antibody immunoprecipitation against different Gα protein subtypes. The hallucinogenic drugs (±)DOI, TCB-2, and LSD activated both Gq/11 and Gi1 proteins through 5-HT2ARs. In contrast, the non-hallucinogenic (±)DOI analogous Ariadne and the LSD analogous agonists 2-Br-LSD and lisuride, at similar concentrations, were inactive in 5-HT2AR-mediated activation of Gi1 proteins whereas activated Gq/11 proteins. Gi2, Go, Gq/11, Gs, and Gz proteins were also triggered by the agonists but through receptor targets other than 5-HT2ARs. The findings were confirmed using 5-HT2AR knock-out mouse brain tissue. The alkylating agent NEM attenuated agonist-mediated Gi1 protein activation with null effect on transduction through Gq/11 proteins, supporting the involvement of inhibitory G proteins in the activity of hallucinogenic 5-HT2AR drugs. In conclusion, Gi1 protein recruitment in human brain may be associated with the psychedelic properties of 5-HT2AR agonists. The results suggest the existence of differential signaling consistent with functional selectivity in the 5-HT2AR coupling to G proteins in the human brain, although a larger panel of drugs should be tested. These findings may help explain the differential behavioral responses elicited by psychedelic and non-psychedelic 5-HT2AR agonists.