Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides
Abstract
Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide, which is recognized as a critical mediator of complimentary, stress-related endocrine, autonomic, and behavioral responses in mammalian species. CRF belongs to a family of structurally related peptides including frogskin sauvagine and fish urotensin I. The effects of CRF and related peptides are mediated by two distinct receptors, which differ in their anatomical distribution, as well as in their pharmacological characteristics. In addition, CRF is bound with high affinity by a CRF binding protein (CRF-BP), which is a putative inhibitor of CRF action. CRF is probably not the sole endogenous ligand for CRF receptors or the CRF-BP, since a second mammalian member of the CRF family, urocortin, has recently been identified. This article describes recent findings with respect to CRF, its receptors, binding protein, and CRF-related peptides, which provide further insights into the role and mechanisms of CRF action in stress responses.
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CRF plays key role in orchestrating endocrine, behavioral, and GI responses to stress.
“CRF is a 41 amino-acid residue peptide that plays a key role in orchestrating the endocrine, behavioral, and GI responses to stress (for review, see [327][328][329]).”
From Anxiety, depression, and the microbiome: A role for gut peptides (2018) · cites this paper as [328]
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“The anterior pituitary is vascularized by the hypophyseal portal vessels that arise from the median eminence capillaries and deliver hypothalamic hormones to the adenohypophyseal corticotroph cells where CRH interacts with its receptor resulting in the stimulation and secretion of adrenocorticotropic hormone (ACTH) an…”
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“There are several CRH receptor subtypes described to date; CRH receptor type 1 and CRH receptor type 2, which can exist as several splice variants, see (37, 56).”
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“CRF was Wrst isolated for its ability to stimulate ACTH secretion in mammals (Turnbull and Rivier, 1997; Vale et al., 1981) and regulation of ACTH by CRF is considered to be the primary hypophysiotropic role for this peptide (Vale et al., 1997).”
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“, 1955) where it stimulates glucocorticoid synthesis and secretion form the adrenal cortex (Turnbull and Rivier, 1997).”
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“It has been hypothesized that interactions between CRF and membrane-associated CRF-BP in the brain are important in maintaining synaptic CRF concentrations (Turnbull and Rivier, 1997).”
BackgroundDistribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain
Kőrösi, A., Veening, J. G., Kozicz, T., Henckens, M. J. A. G., Dederen, J., Groenink, L., van der Gugten, J., Olivier, B., & Roubos, E. W. (2006) · Brain Research · doi:10.1016/j.brainres.2005.12.034 · Cited by 72 · see citing works
“The E – WN Ucn1 acts through both CRF1 and CRF2 receptors but has a strong preference for CRF2 (Potter et al., 1994; Turnbull and Rivier, 1997; Reul and Holsboer, 2002).”
Stress neuropeptides evoke epithelial responses via mast cell activation in the rat colon
Santos, J., Yates, D. A., Guilarte, M., Vicario, M., Alonso, C., & Perdue, M. H. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.07.002 · Cited by 68 · see citing works
Turnbull, A. V., Prehar, S., Kennedy, A. R., Little, R. A., & Hopkins, S. J. (2003) · Endocrinology · doi:10.1210/en.2002-220964 · Cited by 66 · see citing works
“Although AVP is able to induce ACTH secretion and is also released in the pituitary by neurons direct from the PVN, CRF is considered to constitute the major ACTH secretagogue in rodents (1).”
BackgroundSelf-citationStress hormones mediate developmental plasticity in vertebrates with complex life cycles
Denver, R. J. (2021) · Neurobiology of Stress · doi:10.1016/j.ynstr.2021.100301 · Cited by 69 · see citing works
Janssen, D., & Kozicz, T. (2013) · Frontiers in Endocrinology · doi:10.3389/fendo.2013.00028 · Cited by 65 · see citing works
“Upon exposure to a stressor, the HPA-axis is activated by the release of CRF into portal vessels and subsequently acts upon the CRFR1 located in the anterior pituitary (Turnbull and Rivier, 1997; Vale et al., 1997).”
BackgroundWeninger, S. C. (2000) · Endocrinology · doi:10.1210/en.141.1.256 · Cited by 65 · see citing works
“It is the most recent addition to the CRH family of peptides, which also includes frog sauvagine and fish urotensin (2).”
BackgroundChen, C., & Fernald, R. D. (2008) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2008.04.003 · Cited by 63 · see citing works
“In addition to its well studied effects in mediating the whole body stress response, CRF influences a wide spectrum of processes in both the central nervous system and in the periphery, underscoring its role in integrating diverse physiological systems in mammals (Turnbull and Rivier, 1997; Bale and Vale, 2004).”
BackgroundUrocortin in the ventromedial hypothalamic nucleus acts as an inhibitor of feeding behavior in rats
Ohata, H., Suzuki, K. S., Oki, Y., & Shibasaki, T. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02378-1 · Cited by 64 · see citing works
Boorse, G. C., Crespi, E. J., Dautzenberg, F. M., & Denver, R. J. (2005) · Endocrinology · doi:10.1210/en.2005-0497 · Cited by 61 · see citing works
“C factor (CRF) was first isolated from the sheep hypothalamus as a potent secretagogue for pituitary ACTH (1) and has since been shown to mediate endocrine, autonomic, behavioral, and immune responses to stress (2).”
BackgroundAmiel‐Tison, C., CABROL, D., Denver, R. J., Jarreau, P., Papiernik, E., & Piazza, P. V. (2004) · Early Human Development · doi:10.1016/j.earlhumdev.2004.03.007 · Cited by 58 · see citing works
“CRH is a 41amino-acid polypeptide first isolated for its ability to stimulate ACTH secretion in mammals [33,34].”
BackgroundChronic Pain and Comorbid Emotional Disorders: Neural Circuitry and Neuroimmunity Pathways
Li, M. H., She, K., Zhu, P., Li, Z., Liu, J., Luo, F., & Ye, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26020436 · Cited by 65 · see citing works
“CRH and its receptors are located in many areas of the brain outside the hypothalamus, including parts of the limbic system, as well as in the brainstem and spinal cord’s central arousal sympathetic system (LC/NE) [25].”
Marini, F., Pozzato, C., Andreetta, V., Jansson, B., Arban, R., Domenici, E., & Carboni, L. (2005) · Brain Research · doi:10.1016/j.brainres.2005.10.002 · Cited by 57 · see citing works
Urocortin in the synovial tissue of patients with rheumatoid arthritis
Uzuki, M., Sasano, H., Muramatsu, Y., et al. (2001) · Clinical Science · doi:10.1042/cs1000577 · Cited by 58 · see citing works
Kozicz, T., Li, M., & Areviura, A. (2001) · Stress · doi:10.3109/10253890109115724 · Cited by 58 · see citing works
Turnbull, A. V., Vaughan, J. M., Rivier, J., Vale, W., & RIVIER, C. L. (1999) · Endocrinology · doi:10.1210/endo.140.1.6419 · Cited by 58 · see citing works
“CRF belongs to a family of structurally related peptides, including amphibian sauvagine and piscine urotensin I (4, 5).”
Self-citationCorticotropin-releasing factor receptor type 1 and type 2 interaction in irritable bowel syndrome
Nozu, T., & Okumura, T. (2015) · Journal of Gastroenterology · doi:10.1007/s00535-015-1086-8 · Cited by 59 · see citing works
“Stress induces behavioral, neuroendocrine, and autonomic responses, and corticotropin-releasing factor (CRF) is the main mediator of these responses in the brain–gut axis [7–13].”
BackgroundUrocortin and Corticotropin-Releasing Factor Receptor Expression in Normal Cycling Human Ovaries1
Muramatsu, Y., Sugino, N., SUZUKI, T. A., Totsune, K., Takahashi, K., Tashiro, A., Hongo, M., Oki, Y., & Sasano, H. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.3.7299 · Cited by 60 · see citing works
Corticotropin-releasing factor receptor 1-deficient mice do not develop postoperative gastric ileus
Luckey, A. E., Wang, L., Jamieson, P. M., Basa, N. R., Million, M., Czimmer, J., Vale, W., & Taché, Y. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)01069-2 · Cited by 56 · see citing works
- Authors
- Turnbull, A. V., & Rivier, C.
- Affiliations
- Salk Institute for Biological Studies (US)
- Venue
- Experimental Biology and Medicine
- Publisher
- Frontiers Media SA
- Published
- 1997-05-01
- Volume
- 215
- Issue
- 1
- Pages
- 1-10
- ISSN
- 0071-3384 (ISSN-L)
- 1535-3702
- 1535-3699
- OpenAlex
- W2334462456
- Cited by
- 256
- References
- 0
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 2 · 2014: 9 · 2013: 10 · 2012: 13
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH051774, NIMH51774)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDDK-26741)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD013527, NICHD-13527)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- corticotropin-releasing factor, CRF receptors, CRF-binding protein, urocortin, stress response, endocrine stress response, sauvagine, urotensin I, neuropeptides, autonomic stress response, behavioral stress response
- MeSH terms
- Adrenocorticotropic Hormone, Amino Acid Sequence, Animals, Carrier Proteins, Corticotropin-Releasing Hormone, Humans, Luteinizing Hormone, Molecular Sequence Data, Neuropeptides, Stress, Physiological, Receptors, Corticotropin-Releasing Hormone
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