Hallucinogens induce a specific barcode of phosphorylation on the serotonin2A receptor that underlies a weaker receptor desensitization and internalization
Receptors & Clinical Investigation – September 27, 2014
Source: OpenAlex
Summary
A major neuroscience puzzle is unravelled: why certain psychedelics cause hallucinations while others don't. Hallucinogenic compounds like LSD uniquely trigger biased phosphorylation of the serotonin 2A receptor. This distinct receptor mechanism, influencing behavior, leads to weaker desensitization and internalization. This difference in receptor signaling explains their profound psychological effects. These insights advance our understanding of neurotransmitter receptor influence on behavior, crucial for psychology and drug studies, detailing receptor mechanisms.
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.