Paradoxical trafficking and regulation of 5-HT(2A) receptors by agonists and antagonists.
5-Hydroxytryptamine(2A) (serotonin(2A), 5-HT(2A)) receptors are important for many physiologic processes including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. A large number of pharmaceutical agents mediate their actions, at least in part, by modulating the number and/or activity of 5-HT(2A) receptors. Drugs with action at 5-HT(2A) receptors are used in the treatment of many disorders, including schizophrenia, depression, and anxiety disorders. This review summarizes over two decades of research on the regulation of 5-HT(2A) receptors and provides a comprehensive review of numerous in vivo studies describing the paradoxical phenomenon of 5-HT(2A) receptor down-regulation by chronic treatment with antidepressants and antipsychotics. In addition, studies reporting antagonist-induced internalization of 5-HT(2A) receptors and other G protein-coupled receptors will be highlighted as a possible mechanism to explain this paradoxical down-regulation. Finally, a review of the cellular and molecular mechanisms that may be responsible for agonist-mediated desensitization and internalization of 5-HT(2A) receptors will be presented.
Gray
J A
JA
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4935, USA.
Roth
B L
BL
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D021381:Protein Transport / Q000187:drug effects* / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D019204:GTP-Binding Proteins