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Corticotropin-releasing hormone

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CRH
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCRH, CRF, CRH1, corticotropin releasing hormone
External IDsOMIM: 122560; MGI: 88496; HomoloGene: 599; GeneCards: CRH; OMA:CRH - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1392

12918

Ensembl

ENSG00000147571

ENSMUSG00000049796

UniProt

P06850

Q8CIT0

RefSeq (mRNA)

NM_000756

NM_205769

RefSeq (protein)

NP_000747

NP_991338

Location (UCSC)Chr 8: 66.18 – 66.18 MbChr 3: 19.75 – 19.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene.[5] Its main function is the stimulation of the pituitary synthesis of adrenocorticotropic hormone (ACTH), as part of the hypothalamic–pituitary–adrenal axis (HPA axis).

Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide derived from a 196-amino acid preprohormone. CRH is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress. Increased CRH production has been observed to be associated with Alzheimer's disease and major depression,[6] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[5]

In addition to being produced in the hypothalamus, CRH is also synthesized in peripheral tissues, such as T lymphocytes, and is highly expressed in the placenta. In the placenta, CRH is a marker that determines the length of gestation and the timing of parturition and delivery. A rapid increase in circulating levels of CRH occurs at the onset of parturition, suggesting that, in addition to its metabolic functions, CRH may act as a trigger for parturition.[5]

A recombinant version for diagnostics is called corticorelin (INN).

Actions and psychopharmacology

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CRH is produced in response to stress, predominantly by parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and is released at the median eminence from neurosecretory terminals of these neurons into the primary capillary plexus of the hypothalamo-hypophyseal portal system. The portal system carries the CRH to the anterior lobe of the pituitary, where it stimulates corticotropes to secrete adrenocorticotropic hormone (ACTH) and other biologically-active substances (β-endorphin). ACTH stimulates the synthesis of cortisol, glucocorticoids, mineralocorticoids and DHEA.[7]

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.[8]

During chronic stress conditions such as post-traumatic stress disorder (PTSD), blood serum levels of CRH are decreased in combat veterans with PTSD compared to healthy individuals.[9] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function.[10][11][12]

Abnormally high levels of CRH have been found in people with major depression,[13][6] and in the cerebrospinal fluid of people who have committed suicide.[14]

Corticotropin-releasing hormone has been shown to interact with its receptors, corticotropin-releasing hormone receptor 1 (CRFR1) and corticotropin-releasing hormone receptor 2 (CRFR2), in order to induce its effects.[15][16][17][18] Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors.[19] Sex differences have also been observed with respect to both CRH and the receptors that it interacts with. CRFR1 has been shown to exist at higher levels in the female nucleus accumbens, olfactory tubercle, and rostral anteroventral periventricular nucleus (AVPV) when compared to males, while male voles show increased levels of CRFR2 in the bed nucleus of the stria terminalis compared to females.[20]

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder.[21] Another CRH-1 antagonist antalarmin has been researched[citation needed] in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

The activation of the CRH1 receptor has been linked with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by Pfizer, CP-154,526 is under investigation for the potential treatment of alcoholism.[22][23]

Increased CRH production has been observed to be associated with Alzheimer's disease.[6]

Although one action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten the immune system's inflammation response, a process being investigated in multiple sclerosis research.[24]

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[5]

Alpha-helical CRH-(9–41) acts as a CRH antagonist.[25]

Role in parturition

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CRH is synthesized by the placenta and seems to determine the duration of pregnancy.[26]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:[27]

  • Increases levels of dehydroepiandrosterone (DHEA) directly by action on the fetal adrenal gland, and indirectly via the mother's pituitary gland. DHEA has a role in preparing for and stimulating cervical contractions.
  • Increases prostaglandin availability in uteroplacental tissues. Prostaglandins activate cervical contractions.
  • Prior to parturition it may have a role inhibiting contractions, through increasing cAMP levels in the myometrium.

In culture, trophoblast CRH is inhibited by progesterone, which remains high throughout pregnancy. Its release is stimulated by glucocorticoids and catecholamines, which increase prior to parturition lifting this progesterone block.[28]

Structure

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The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981.[29] Its full sequence is:

  • SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.[30]

  • SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII

Role in non-mammalian vertebrates

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In mammals, studies suggest that CRH has no significant thyrotropic effect. However, in representatives of all non-mammalian vertebrates, it has been found that, in addition to its corticotropic function, CRH has a potent thyrotropic function, acting with TRH to control the hypothalamic–pituitary–thyroid axis (TRH has been found to be less potent than CRH in some species).[31][32]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000147571 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049796 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d "Entrez Gene: CRH corticotropin releasing hormone".
  6. ^ a b c Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF (September 1995). "Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression". The American Journal of Psychiatry. 152 (9): 1372–1376. doi:10.1176/ajp.152.9.1372. PMID 7653697.
  7. ^ "Corticotrophin-releasing hormone". 5 September 2012. Society for Endocrinology. Archived from the original on 20 October 2016. Retrieved 9 July 2013.
  8. ^ Daviu N, Bruchas MR, Moghaddam B, Sandi C, Beyeler A (November 2019). "Neurobiological links between stress and anxiety". Neurobiology of Stress. 11: 100191. doi:10.1016/j.ynstr.2019.100191. PMC 6712367. PMID 31467945.
  9. ^ Ramos-Cejudo J, Genfi A, Abu-Amara D, Debure L, Qian M, Laska E, et al. (2021). "CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans". Psychiatric Research and Clinical Practice. 3 (4): 153–162. doi:10.1176/appi.prcp.20210017. PMC 8764614. PMID 35211666.
  10. ^ Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. (October 2015). "Post-traumatic stress disorder". Nature Reviews. Disease Primers. 1: 15057. doi:10.1038/nrdp.2015.57. PMID 27189040. S2CID 1510508.
  11. ^ Zorrilla EP, Logrip ML, Koob GF (April 2014). "Corticotropin releasing factor: a key role in the neurobiology of addiction". Frontiers in Neuroendocrinology. 35 (2): 234–244. doi:10.1016/j.yfrne.2014.01.001. PMC 4213066. PMID 24456850.
  12. ^ Cooper O, Bonert V, Moser F, Mirocha J, Melmed S (June 2017). "Altered Pituitary Gland Structure and Function in Posttraumatic Stress Disorder". Journal of the Endocrine Society. 1 (6): 577–587. doi:10.1210/js.2017-00069. PMC 5686623. PMID 29264511.
  13. ^ Galard R, Catalán R, Castellanos JM, Gallart JM (March 2002). "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test". Biological Psychiatry. 51 (6): 463–468. doi:10.1016/s0006-3223(01)01273-2. PMID 11922880. S2CID 23478346.
  14. ^ Arató M, Bánki CM, Bissette G, Nemeroff CB (February 1989). "Elevated CSF CRF in suicide victims". Biological Psychiatry. 25 (3): 355–359. doi:10.1016/0006-3223(89)90183-2. PMID 2536563. S2CID 19665375.
  15. ^ Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, et al. (December 1999). "A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes". Molecular Endocrinology. 13 (12): 2189–2202. doi:10.1210/mend.13.12.0391. PMID 10598591.
  16. ^ Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, et al. (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–1446. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932. S2CID 6235036.
  17. ^ Ramot A, Jiang Z, Tian JB, Nahum T, Kuperman Y, Justice N, et al. (March 2017). "Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress". Nature Neuroscience. 20 (3): 385–388. doi:10.1038/nn.4491. PMID 28135239. S2CID 5017743.
  18. ^ Bale TL, Vale WW (10 February 2004). "CRF and CRF receptors: role in stress responsivity and other behaviors". Annual Review of Pharmacology and Toxicology. 44 (1): 525–557. doi:10.1146/annurev.pharmtox.44.101802.121410. PMID 14744257.
  19. ^ Wang HL, Morales M (July 2008). "Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons". The Journal of Comparative Neurology. 509 (3): 302–318. doi:10.1002/cne.21751. PMC 2575090. PMID 18478589.
  20. ^ Rosinger ZJ, Jacobskind JS, De Guzman RM, Justice NJ, Zuloaga DG (June 2019). "A sexually dimorphic distribution of corticotropin-releasing factor receptor 1 in the paraventricular hypothalamus". Neuroscience. 409: 195–203. doi:10.1016/j.neuroscience.2019.04.045. PMC 6897333. PMID 31055007.
  21. ^ "Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder". ClinicalTrials.gov. 1 August 2008. Retrieved 3 August 2008.
  22. ^ "Drug Has Potential To Prevent Alcoholics From Relapsing". Science News. ScienceDaily. 2 August 2008. Retrieved 9 August 2008.
  23. ^ Pastor R, McKinnon CS, Scibelli AC, Burkhart-Kasch S, Reed C, Ryabinin AE, et al. (July 2008). "Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin1-independent mechanism". Proceedings of the National Academy of Sciences of the United States of America. 105 (26): 9070–9075. Bibcode:2008PNAS..105.9070P. doi:10.1073/pnas.0710181105. PMC 2449366. PMID 18591672.
  24. ^ Paul WE (September 1993). "Infectious diseases and the immune system". Scientific American. 269 (3): 90–97. Bibcode:1993SciAm.269c..90P. doi:10.1038/scientificamerican0993-90. PMID 8211095.
  25. ^ Santos J, Saunders PR, Hanssen NP, Yang PC, Yates D, Groot JA, et al. (August 1999). "Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat". The American Journal of Physiology. 277 (2): G391–G399. doi:10.1152/ajpgi.1999.277.2.G391. PMID 10444454. S2CID 4457633.
  26. ^ Guillemin R, Burgus R (November 1972). "The hormones of the hypothalamus". Scientific American. 227 (5): 24–33. Bibcode:1972SciAm.227e..24G. doi:10.1038/scientificamerican1172-24. PMID 4145789. Archived from the original on 27 June 2012. Retrieved 3 August 2008.
  27. ^ Lye S, Challis JR (2001). "Chapter 12: Parturition". In Bocking AD, Harding R (eds.). Fetal growth and development. Cambridge, UK: Cambridge University Press. pp. 241–266. ISBN 978-0-521-64543-0.
  28. ^ Jones SA, Brooks AN, Challis JR (April 1989). "Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta". The Journal of Clinical Endocrinology and Metabolism. 68 (4): 825–830. doi:10.1210/jcem-68-4-825. PMID 2537843.
  29. ^ Vale W, Spiess J, Rivier C, Rivier J (September 1981). "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin". Science. 213 (4514): 1394–1397. Bibcode:1981Sci...213.1394V. doi:10.1126/science.6267699. PMID 6267699.
  30. ^ Chrousos GP, Schuermeyer TH, Doppman J, Oldfield EH, Schulte HM, Gold PW, et al. (March 1985). "NIH conference. Clinical applications of corticotropin-releasing factor". Annals of Internal Medicine. 102 (3): 344–358. doi:10.7326/0003-4819-102-3-344. PMID 2982307.
  31. ^ Seasholtz AF, Valverde RA, Denver RJ (October 2002). "Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals". The Journal of Endocrinology. 175 (1): 89–97. doi:10.1677/joe.0.1750089. PMID 12379493.
  32. ^ De Groef B, Van der Geyten S, Darras VM, Kühn ER (March 2006). "Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates". General and Comparative Endocrinology. 146 (1): 62–68. doi:10.1016/j.ygcen.2005.10.014. PMID 16337947.

Further reading

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