Hallucinogens induce a specific barcode of phosphorylation on the serotonin2A receptor that underlies a weaker receptor desensitization and internalization

The serotonin 2A receptor is a key target of psychedelic hallucinogens like LSD, mescaline, and psilocybin, which can mimic schizophrenia symptoms and are used to study the disorder. A paradox exists: some agonists with similar binding strength and activity, such as lisuride and ergotamine, lack hallucinogenic effects. A recent study showed that hallucinogenic agonists cause biased phosphorylation of the receptor, leading to weaker desensitization and internalization compared to non-hallucinogenic agonists, suggesting a mechanism for their distinct psychoactive effects.

Study at a glance

Abstract

The serotonin (5-Hydroxytryptamine, 5-HT) 2A receptor represents one of the most striking examples where functional selectivity (or ligand-biased signaling) is transduced in distinct behaviours. This receptor is the primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline and psilocybin, which reproduce some of the core symptoms of schizophrenia and are often used to probe the disease. Why only some 5-HT 2A receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and agonist activity (e.g. lisuride and ergotamine) lack such a psychoactive activity remains an incompletely resolved paradox. In a recent paper published in Molecular and Cellular Proteomics (doi: 10.1074/mcp.M113.036558) we demonstrated a biased phosphorylation of the 5-HT 2A receptor in response to hallucinogenic versus non-hallucinogenic agonists that leads to a weaker receptor desensitization and internalization by hallucinogens.