title: Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.
abstract: The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.
authors.affiliation: Departments of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Coste
authors.forename: R A
authors.initials: RA
authors.lastname: Kesterson
authors.forename: K A
authors.initials: KA
authors.lastname: Heldwein
authors.forename: S L
authors.initials: SL
authors.lastname: Stevens
authors.forename: A D
authors.initials: AD
authors.lastname: Heard
authors.forename: J H
authors.initials: JH
authors.lastname: Hollis
authors.forename: S E
authors.initials: SE
authors.lastname: Murray
authors.forename: J K
authors.initials: JK
authors.lastname: Hill
authors.forename: G A
authors.initials: GA
authors.lastname: Pantely
authors.forename: A R
authors.initials: AR
authors.lastname: Hohimer
authors.forename: D C
authors.initials: DC
authors.lastname: Hatton
authors.forename: T J
authors.initials: TJ
authors.lastname: Phillips
authors.forename: D A
authors.initials: DA
authors.lastname: Finn
authors.forename: M J
authors.initials: MJ
authors.lastname: Low
authors.forename: M B
authors.initials: MB
authors.lastname: Rittenberg
authors.forename: P
authors.initials: P
authors.lastname: Stenzel
authors.forename: M P
authors.initials: MP
authors.lastname: Stenzel-Poore
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000223:Adaptation, Psychological / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000235:genetics; D002319:Cardiovascular System / Q000378:metabolism / Q000503:physiopathology*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D004452:Echocardiography; D005106:Exploratory Behavior; D005260:Female; D018390:Gene Targeting; D006120:Grooming; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000097:blood / Q000235:genetics; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D054832:Urocortins; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone