title: α2 Adrenergic Receptor Trafficking as a Therapeutic Target in Antidepressant Drug Action.
abstract: Antidepressant drugs remain poorly understood, especially with respect to pharmacological mechanisms of action. This lack of knowledge results from the extreme complexity inherent to psychopharmacology, as well as to a corresponding lack of knowledge regarding depressive disorder pathophysiology. While the final analysis is likely to be multifactorial and heterogeneous, compelling evidence exists for upregulation of brain α2 adrenergic receptors (ARs) in depressed patients. This evidence has sparked a line of research into actions of a particular antidepressant drug class, the tricyclic antidepressants (TCAs), as direct ligands at α(2A)ARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at α(2A)ARs. Importantly, TCA-induced α(2A)AR/arrestin recruitment leads to receptor endocytosis and downregulation of α(2A)AR expression with prolonged exposure. These findings represent a novel mechanism linking α(2)AR trafficking with antidepressant pharmacology.
authors.affiliation: Department of Biology and Chemistry, Morehead State University, Morehead, Kentucky, USA. Electronic address: c.cottingham@moreheadstate.edu.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cottingham
authors.affiliation: Department of Biology and Chemistry, Morehead State University, Morehead, Kentucky, USA.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Ferryman
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Electronic address: qinwang@uab.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000196:embryology; D002465:Cell Movement; D003863:Depression / Q000188:drug therapy*; D015195:Drug Design; D004705:Endocytosis; D006801:Humans; D008024:Ligands; D051379:Mice; D021381:Protein Transport; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2
keywords: Antidepressant; Arrestin; Downregulation; Endocytosis; α(2) Adrenergic receptor