title: Pharmacological blockade of a β(2)AR-β-arrestin-1 signaling cascade prevents the accumulation of DNA damage in a behavioral stress model.
abstract: Chronic stress is known to have a profound negative impact on human health and has been suggested to influence a number of disease states. However, the mechanisms underlying the deleterious effects of stress remain largely unknown. Stress is known to promote the release of epinephrine, a catecholamine stress hormone that binds to β(2)-adrenergic receptors (β(2)ARs) with high affinity. Our previous work has demonstrated that chronic stimulation of a β(2)AR-β-arrestin-1-mediated signaling pathway by infusion of isoproterenol suppresses p53 levels and impairs genomic integrity. In this pathway, β-arrestin-1, which is activated via β(2)ARs, facilitates the AKT-mediated activation of Mdm2 and functions as a molecular scaffold to promote the binding and degradation of p53 by the E3-ubiquitin ligase, Mdm2. Here, we show that chronic restraint stress in mice recapitulates the effects of isoproterenol infusion to reduce p53 levels and results in the accumulation of DNA damage in the frontal cortex of the brain, two effects that are abrogated by the β-blocker, propranolol and by genetic deletion of β-arrestin-1. These data suggest that the β(2)AR-β-arrestin-1 signaling pathway may represent an attractive therapeutic target to prevent some of the negative consequences of stress in the treatment of stress-related disorders.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Makoto R
authors.initials: MR
authors.lastname: Hara
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004837:Epinephrine / Q000378:metabolism; D006657:Histones / Q000276:immunology; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D000911:Antibodies, Monoclonal; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D006657:Histones; D011944:Receptors, Androgen; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C475961:gamma-H2AX protein, mouse; D011433:Propranolol; D004837:Epinephrine
keywords: DNA damage; adrenergic receptor; arrestin; stress; β-blocker