Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

Sarah C. Coste, Robert A. Kesterson, Kurt A. Heldwein, Susan L. Stevens, Amanda D. Heard, Jacob H. Hollis, Susan Murray, Jennifer K. Hill, George Pantely, Alan (Roger) Hohimer, Daniel C. Hatton, Tamara Phillips, Deborah (Deb) Finn, Malcolm J. Low, Marvin Rittenberg, Peter Stenzel, Mary Stenzel-Poore

Research output: Contribution to journalArticle

514 Citations (Scopus)

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 (refs 4,5). 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, 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.

Original languageEnglish (US)
Pages (from-to)403-409
Number of pages7
JournalNature Genetics
Volume24
Issue number4
DOIs
StatePublished - Apr 2000

Fingerprint

Corticotropin-Releasing Hormone Receptors
Urocortins
Blood Pressure
Corticotropin-Releasing Hormone
Psychological Adaptation
Tissue Distribution
Corticosterone
Adrenocorticotropic Hormone
Homeostasis
Anxiety
Central Nervous System
Hemodynamics

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. / Coste, Sarah C.; Kesterson, Robert A.; Heldwein, Kurt A.; Stevens, Susan L.; Heard, Amanda D.; Hollis, Jacob H.; Murray, Susan; Hill, Jennifer K.; Pantely, George; Hohimer, Alan (Roger); Hatton, Daniel C.; Phillips, Tamara; Finn, Deborah (Deb); Low, Malcolm J.; Rittenberg, Marvin; Stenzel, Peter; Stenzel-Poore, Mary.

In: Nature Genetics, Vol. 24, No. 4, 04.2000, p. 403-409.

Research output: Contribution to journalArticle

Coste, SC, Kesterson, RA, Heldwein, KA, Stevens, SL, Heard, AD, Hollis, JH, Murray, S, Hill, JK, Pantely, G, Hohimer, AR, Hatton, DC, Phillips, T, Finn, DD, Low, MJ, Rittenberg, M, Stenzel, P & Stenzel-Poore, M 2000, 'Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2', Nature Genetics, vol. 24, no. 4, pp. 403-409. https://doi.org/10.1038/74255
Coste, Sarah C. ; Kesterson, Robert A. ; Heldwein, Kurt A. ; Stevens, Susan L. ; Heard, Amanda D. ; Hollis, Jacob H. ; Murray, Susan ; Hill, Jennifer K. ; Pantely, George ; Hohimer, Alan (Roger) ; Hatton, Daniel C. ; Phillips, Tamara ; Finn, Deborah (Deb) ; Low, Malcolm J. ; Rittenberg, Marvin ; Stenzel, Peter ; Stenzel-Poore, Mary. / Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. In: Nature Genetics. 2000 ; Vol. 24, No. 4. pp. 403-409.
@article{04089d99068f41af91b360d40ef1216b,
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 (refs 4,5). 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, 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.",
author = "Coste, {Sarah C.} and Kesterson, {Robert A.} and Heldwein, {Kurt A.} and Stevens, {Susan L.} and Heard, {Amanda D.} and Hollis, {Jacob H.} and Susan Murray and Hill, {Jennifer K.} and George Pantely and Hohimer, {Alan (Roger)} and Hatton, {Daniel C.} and Tamara Phillips and Finn, {Deborah (Deb)} and Low, {Malcolm J.} and Marvin Rittenberg and Peter Stenzel and Mary Stenzel-Poore",
year = "2000",
month = "4",
doi = "10.1038/74255",
language = "English (US)",
volume = "24",
pages = "403--409",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2

AU - Coste, Sarah C.

AU - Kesterson, Robert A.

AU - Heldwein, Kurt A.

AU - Stevens, Susan L.

AU - Heard, Amanda D.

AU - Hollis, Jacob H.

AU - Murray, Susan

AU - Hill, Jennifer K.

AU - Pantely, George

AU - Hohimer, Alan (Roger)

AU - Hatton, Daniel C.

AU - Phillips, Tamara

AU - Finn, Deborah (Deb)

AU - Low, Malcolm J.

AU - Rittenberg, Marvin

AU - Stenzel, Peter

AU - Stenzel-Poore, Mary

PY - 2000/4

Y1 - 2000/4

N2 - 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 (refs 4,5). 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, 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.

AB - 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 (refs 4,5). 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, 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.

UR - http://www.scopus.com/inward/record.url?scp=0034087469&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034087469&partnerID=8YFLogxK

U2 - 10.1038/74255

DO - 10.1038/74255

M3 - Article

C2 - 10742107

AN - SCOPUS:0034087469

VL - 24

SP - 403

EP - 409

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -