Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling
Article Meta
-Article Date = 28 January 2026
-Article URL = https://www.nature.com/articles/s41586-025-10061-7
-Article Title = Psychedelics elicit their effects by 5-HT2A receptor-mediated Gi signalling
-Article Image =
Summary
This study combines cryo-electron microscopy, pharmacology, molecular dynamics and behavioural experiments to show that classic psychedelics (for example DOI, psilocin, LSD, ariadne) directly engage Gi signalling downstream of the serotonin 5-HT2A receptor (5-HT2A R), not only the widely emphasised Gq pathway. The authors resolved multiple cryo-EM structures of 5-HT2A R bound to psychedelics in complex with G i and G q proteins, mapped ligand–receptor interactions that favour Gi coupling, and validated the functional consequences with biosensor assays (BRET, TRUPATH, GloSensor), mutational analysis and mouse models of behaviour.
Key experimental points include structural models for DOI- and psilocin-bound 5-HT2A R–G i complexes (PDB codes provided), demonstration that psychedelics trigger Gi-dependent cellular gene responses, and demonstration in corticosterone-induced mouse models that some antidepressant- and behaviour-related effects require Gi signalling (tests included open-field, forced-swim and head-twitch responses). Structure-guided mutagenesis and MD simulations identify residues (for example F3396.51, I1633.40, S2425.46) and binding-mode features that bias coupling toward Gi vs Gq. The authors also screened DOI derivatives for biased signalling profiles and report pharmacological tools that modify behavioural outcomes.
Key Points
- Psychedelics can directly activate Gi signalling through the 5-HT2A receptor; cryo-EM structures show 5-HT2A R bound to ligands with Gi and Gq proteins.
- Functional biosensor assays (GloSensor, TRUPATH, BRET) confirm robust Gi pathway activation by several psychedelics alongside Gq signalling.
- Mutational mapping and molecular dynamics identify receptor residues and ligand orientations that determine Gi versus Gq coupling bias.
- Behavioural experiments in mice link Gi signalling to key psychedelic-induced behavioural and antidepressant-like effects; Gi blockade (for example pertussis toxin) alters outcomes.
- Structure-based ligand design produced derivatives with altered signalling bias, offering a route to separate therapeutic benefits from hallucinogenic effects.
- Data resources: cryo-EM maps and PDB entries (9LL7–9LLB) and RNA-seq (CRA031070) are deposited and source data are provided with the paper.
Context and relevance
This paper is significant because it challenges and refines the mechanistic narrative in psychedelic research: 5-HT2A R-mediated effects are not solely a Gq story. Demonstrating direct Gi engagement helps explain diverse cellular and behavioural readouts seen in recent literature and opens practical avenues for drug discovery — particularly for designing compounds with therapeutic efficacy without strong hallucinogenic activity. The work ties high-resolution structural insight to functional assays and animal behaviour, which is relatively rare and valuable for translational neuroscience and psychopharmacology.
Why should I read this?
If you care about how psychedelics might become real, safe medicines (or simply want to know what actually happens at the receptor), this paper is a game-changer. It turns a prevailing assumption on its head, gives you atom-level structures, shows the functional consequences and even points to routes for designing better drugs. Quick take: it’s heavy on data but the implications for treatment design and for interpreting past studies are huge — worth the read.
Author note
Punchy: multi-technique, high-confidence work. If you follow neuroscience, psychopharmacology or drug design, dig into the figures and the mutational/behavioural data — they matter for what comes next in psychedelic therapeutics.