Biology:Corticotropin-releasing hormone

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Short description: Mammalian protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[1] 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,[2] and autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[1]

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.[1]

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

Actions and psychopharmacology

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.[3]

In the short term, CRH can suppress appetite, increase subjective feelings of anxiety, and perform other functions like boosting attention.[4]

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.[5] It is believed that chronic stress enhances the negative feedback inhibition of the HPA axis, resulting in lower CRH levels and HPA function.[6][7][8]

Abnormally high levels of CRH have been found in people with major depression,[9][2] and in the cerebrospinal fluid of people who have committed suicide.[10]

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.[11][12][13] Injection of CRH into the rodent paraventricular nucleus of the hypothalamus (PVN) can increase CRFR1 expression, with increased expression leading to depression-like behaviors.[14] 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.[15]

The CRH-1 receptor antagonist pexacerfont is currently under investigation for the treatment of generalized anxiety disorder.[16] 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.[17][18]

Increased CRH production has been observed to be associated with Alzheimer's disease.[2]

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.[19]

Autosomal recessive hypothalamic corticotropin deficiency has multiple and potentially fatal metabolic consequences including hypoglycemia.[1]

Alpha-helical CRH-(9–41) acts as a CRH antagonist.[20]

Role in parturition

CRH is synthesized by the placenta and seems to determine the duration of pregnancy.[21]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:[22]

  • 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.[23]

Structure

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981.[24] Its full sequence is:

  • SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.[25]

  • SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII

Role in non-mammalian vertebrates

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).[26][27]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 "Entrez Gene: CRH corticotropin releasing hormone". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1392. 
  2. ↑ 2.0 2.1 2.2 "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. September 1995. doi:10.1176/ajp.152.9.1372. PMID 7653697. 
  3. ↑ "Corticotrophin-releasing hormone". 5 September 2012. Society for Endocrinology. http://www.yourhormones.info/hormones/corticotrophinreleasing_hormone.aspx. 
  4. ↑ "Neurobiological links between stress and anxiety". Neurobiology of Stress 11: 100191. November 2019. doi:10.1016/j.ynstr.2019.100191. PMID 31467945. 
  5. ↑ "CRF serum levels differentiate PTSD from healthy controls and TBI in military veterans". Psychiatric Research and Clinical Practice 3 (4): 153–162. 2021. doi:10.1176/appi.prcp.20210017. PMID 35211666. 
  6. ↑ "Post-traumatic stress disorder". Nature Reviews. Disease Primers 1: 15057. October 2015. doi:10.1038/nrdp.2015.57. PMID 27189040. 
  7. ↑ "Corticotropin releasing factor: a key role in the neurobiology of addiction". Frontiers in Neuroendocrinology 35 (2): 234–244. April 2014. doi:10.1016/j.yfrne.2014.01.001. PMID 24456850. 
  8. ↑ "Altered Pituitary Gland Structure and Function in Posttraumatic Stress Disorder". Journal of the Endocrine Society 1 (6): 577–587. June 2017. doi:10.1210/js.2017-00069. PMID 29264511. 
  9. ↑ "Plasma corticotropin-releasing factor in depressed patients before and after the dexamethasone suppression test". Biological Psychiatry 51 (6): 463–468. March 2002. doi:10.1016/s0006-3223(01)01273-2. PMID 11922880. 
  10. ↑ "Elevated CSF CRF in suicide victims". Biological Psychiatry 25 (3): 355–359. February 1989. doi:10.1016/0006-3223(89)90183-2. PMID 2536563. 
  11. ↑ "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. December 1999. doi:10.1210/mend.13.12.0391. PMID 10598591. 
  12. ↑ "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology 36 (10): 1439–1446. October 1997. doi:10.1016/S0028-3908(97)00098-1. PMID 9423932. 
  13. ↑ "Hypothalamic CRFR1 is essential for HPA axis regulation following chronic stress". Nature Neuroscience 20 (3): 385–388. March 2017. doi:10.1038/nn.4491. PMID 28135239. 
  14. ↑ "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. July 2008. doi:10.1002/cne.21751. PMID 18478589. 
  15. ↑ "A sexually dimorphic distribution of corticotropin-releasing factor receptor 1 in the paraventricular hypothalamus". Neuroscience 409: 195–203. June 2019. doi:10.1016/j.neuroscience.2019.04.045. PMID 31055007. 
  16. ↑ "Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder". ClinicalTrials.gov. 2008-08-01. http://www.clinicaltrials.gov/ct/show/NCT00481325?order=31. 
  17. ↑ "Drug Has Potential To Prevent Alcoholics From Relapsing". Science News. ScienceDaily. 2008-08-02. https://www.sciencedaily.com/releases/2008/07/080730175518.htm. 
  18. ↑ "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. July 2008. doi:10.1073/pnas.0710181105. PMID 18591672. Bibcode: 2008PNAS..105.9070P. 
  19. ↑ "Infectious diseases and the immune system". Scientific American 269 (3): 90–97. September 1993. doi:10.1038/scientificamerican0993-90. PMID 8211095. Bibcode: 1993SciAm.269c..90P. 
  20. ↑ "Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat". The American Journal of Physiology 277 (2): G391–G399. August 1999. doi:10.1152/ajpgi.1999.277.2.G391. PMID 10444454. 
  21. ↑ "The hormones of the hypothalamus". Scientific American 227 (5): 24–33. November 1972. doi:10.1038/scientificamerican1172-24. PMID 4145789. Bibcode: 1972SciAm.227e..24G. http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/Hypothalamus.html#CRH. Retrieved 2008-08-03. 
  22. ↑ "Chapter 12: Parturition". Fetal growth and development. Cambridge, UK: Cambridge University Press. 2001. pp. 241–266. ISBN 978-0-521-64543-0. 
  23. ↑ "Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta". The Journal of Clinical Endocrinology and Metabolism 68 (4): 825–830. April 1989. doi:10.1210/jcem-68-4-825. PMID 2537843. 
  24. ↑ "Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin". Science 213 (4514): 1394–1397. September 1981. doi:10.1126/science.6267699. PMID 6267699. Bibcode: 1981Sci...213.1394V. 
  25. ↑ "NIH conference. Clinical applications of corticotropin-releasing factor". Annals of Internal Medicine 102 (3): 344–358. March 1985. doi:10.7326/0003-4819-102-3-344. PMID 2982307. 
  26. ↑ "Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals". The Journal of Endocrinology 175 (1): 89–97. October 2002. doi:10.1677/joe.0.1750089. PMID 12379493. 
  27. ↑ "Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates". General and Comparative Endocrinology 146 (1): 62–68. March 2006. doi:10.1016/j.ygcen.2005.10.014. PMID 16337947. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: P06850 (Corticoliberin) at the PDBe-KB.



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