title: Agonist-trafficking and hallucinogens.
abstract: Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.
authors.affiliation: Departments of Psychiatry, Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. Javier.Maeso@mssm.edu
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D006213:Hallucinogens / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D006213:Hallucinogens; D011956:Receptors, Cell Surface