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词条 Corticotropin-releasing hormone
释义

  1. Hormonal actions

  2. Psychopharmacology

  3. Role in parturition

  4. Structure

  5. Role in non-mammalian vertebrates

  6. Interactions

  7. See also

  8. References

  9. Further reading

{{Infobox_gene}}

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 the stress response. 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 ACTH, as part of the 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,[1] 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.[2]

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

Hormonal actions

CRH is produced by parvocellular neuroendocrine 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. Although the distal action of CRH is immunosuppression via the action of cortisol, CRH itself can actually heighten inflammation, a process being investigated in multiple sclerosis research.[4]

Psychopharmacology

The CRH-1 receptor antagonist pexacerfont is currently under

investigation for the treatment of generalized anxiety disorder.[5] Another CRH-1 antagonist antalarmin has been researched in animal studies for the treatment of anxiety, depression and other conditions, but no human trials with this compound have been carried out.

Also, abnormally high levels of CRH have been found in the cerebrospinal fluid of people that have committed suicide.[6]

Recent research has linked the activation of the CRH1 receptor 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.[7][8]

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

Role in parturition

CRH is also synthesized by the placenta and seems to determine the duration of pregnancy.[10]

Levels rise towards the end of pregnancy just before birth and current theory suggests three roles of CRH in parturition:[11]

  • 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.[12]

Structure

The 41-amino acid sequence of CRH was first discovered in sheep by Vale et al. in 1981.[13] Its full sequence is:

  • SQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA

The rat and human peptides are identical and differ from the ovine sequence only by 7 amino acids.[14]

  • 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 thyroid axis (TRH has been found to be less potent than CRH in some species).[15][16]

Interactions

Corticotropin-releasing hormone has been shown to interact with corticotropin-releasing hormone receptor 1.[17][18]

See also

  • Corticotropin-releasing hormone receptor
  • ACTH
  • Glucocorticoids
  • Proopiomelanocortin
  • Hypothalamic-pituitary-adrenal axis
  • Cushing's syndrome
  • Addison's disease

References

1. ^{{cite journal |vauthors=Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF | title = Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression | journal = Am J Psychiatry | volume = 152 | issue = 9 | pages = 1372–6 | date = September 1995 | pmid = 7653697 | doi = 10.1176/ajp.152.9.1372 | url = }}
2. ^1 2 {{cite web | title = Entrez Gene: CRH corticotropin releasing hormone| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1392| accessdate = }}
3. ^{{cite web|title=Corticotrophin-releasing hormone|url=http://www.yourhormones.info/hormones/corticotrophinreleasing_hormone.aspx|work=September 5, 2012|publisher=Society for Endocrinology}}
4. ^{{cite journal|last=Paul|first=William E.|title=Infectious Diseases and the Immune System|journal=Scientific American|date=September 1993|page=112|bibcode=1993SciAm.269c..90P|volume=269|doi=10.1038/scientificamerican0993-90|issue=3}}
5. ^{{cite web | url = http://www.clinicaltrials.gov/ct/show/NCT00481325?order=31 | title = Study of Pexacerfont (BMS-562086) in the Treatment of Outpatients With Generalized Anxiety Disorder | date = 2008-08-01 | format = | website = | publisher = ClinicalTrials.gov | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-03}}
6. ^{{cite journal |vauthors=Arató M, Bánki CM, Bissette G, Nemeroff CB | title = Elevated CSF CRF in suicide victims | journal = Biol. Psychiatry | volume = 25 | issue = 3 | pages = 355–9 | year = 1989 | pmid = 2536563 | doi = 10.1016/0006-3223(89)90183-2 }}
7. ^{{cite web | url = https://www.sciencedaily.com/releases/2008/07/080730175518.htm | title = Drug Has Potential To Prevent Alcoholics From Relapsing | date = 2008-08-02 | work = Science News | publisher = ScienceDaily | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-09}}
8. ^{{cite journal |vauthors=Pastor R, McKinnon CS, Scibelli AC, Burkhart-Kasch S, Reed C, Ryabinin AE, Coste SC, Stenzel-Poore MP, Phillips TJ | title = Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: a urocortin1-independent mechanism | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 26 | pages = 9070–5 | date = July 2008 | pmid = 18591672 | pmc = 2449366 | doi = 10.1073/pnas.0710181105 | url = |bibcode = 2008PNAS..105.9070P }}
9. ^{{cite journal |vauthors=Santos J, Saunders PR, Hanssen NP, Yang PC, Yates D, Groot JA, Perdue MH | title = Corticotropin-releasing hormone mimics stress-induced colonic epithelial pathophysiology in the rat | journal = Am. J. Physiol. | volume = 277 | issue = 2 Pt 1 | pages = G391–9 | date = 1 August 1999 | pmid = 10444454 | url = http://ajpgi.physiology.org/cgi/content/abstract/277/2/G391 | doi = 10.1152/ajpgi.1999.277.2.G391 }}
10. ^{{cite journal | url = http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/Hypothalamus.html#CRH | title = Hormones of the Hypothalamus | volume = 227 | issue = 5 | author = Kimball JW | date = 2006-06-15 | format = | journal = Kimball's Biology Pages | pages = 24–33| language = | archiveurl = | archivedate = | quote = | accessdate = 2008-08-03| bibcode = 1972SciAm.227e..24G | doi = 10.1038/scientificamerican1172-24 }}
11. ^{{cite book |vauthors=Lye S, Challis JR |veditors=Bocking AD, Harding R | title = Fetal growth and development | edition = | language = | publisher = Cambridge University Press | location = Cambridge, UK | year = 2001 | origyear = | chapter = Chapter 12: Parturition | pages = 241–266| quote = | isbn = 978-0-521-64543-0 | oclc = | accessdate = }}
12. ^{{cite journal |vauthors=Jones SA, Brooks AN, Challis JR | title = Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta | journal = J. Clin. Endocrinol. Metab. | volume = 68 | issue = 4 | pages = 825–30 | date = April 1989 | pmid = 2537843 | doi = 10.1210/jcem-68-4-825 | url = }}
13. ^{{cite journal |vauthors=Vale W, Spiess J, Rivier C, Rivier J | title = Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin | journal = Science | volume = 213 | issue = 4514 | pages = 1394–7 | date = September 1981 | pmid = 6267699 | doi = 10.1126/science.6267699 | url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=6267699 |bibcode = 1981Sci...213.1394V }}
14. ^{{cite journal |vauthors=Chrousos GP, Schuermeyer TH, Doppman J, Oldfield EH, Schulte HM, Gold PW, Loriaux DL | title = NIH conference. Clinical applications of corticotropin-releasing factor | journal = Annals of Internal Medicine | volume = 102 | issue = 3 | pages = 344–358 | date = March 1985 | pmid = 2982307 | doi = 10.7326/0003-4819-102-3-344 }}
15. ^{{cite journal |vauthors=Seasholtz AF, Valverde RA, Denver RJ | title = Corticotropin-releasing hormone-binding protein: biochemistry and function from fishes to mammals | journal = The Journal of Endocrinology | volume = 175 | issue = 1 | pages = 89–97 | date = October 2002 | pmid = 12379493 | doi = 10.1677/joe.0.1750089 }}
16. ^{{cite journal |vauthors=De Groef B, Van der Geyten S, Darras VM, Kühn ER | title = Role of corticotropin-releasing hormone as a thyrotropin-releasing factor in non-mammalian vertebrates | journal = General and Comparative Endocrinology | volume = 146 | issue = 1 | pages = 62–8 | date = March 2006 | pmid = 16337947 | doi = 10.1016/j.ygcen.2005.10.014 }}
17. ^{{cite journal |vauthors=Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW | title = 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 | journal = Mol. Endocrinol. | volume = 13 | issue = 12 | pages = 2189–202 | date = December 1999 | pmid = 10598591 | doi = 10.1210/mend.13.12.0391 }}
18. ^{{cite journal |vauthors=Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ | title = Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin | journal = Neuropharmacology | volume = 36 | issue = 10 | pages = 1439–46 | date = October 1997 | pmid = 9423932 | doi = 10.1016/S0028-3908(97)00098-1 }}

Further reading

{{Refbegin | 2}}
  • {{cite journal |vauthors=Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, De Felice C, Palumbo M, Petraglia F | title = Placental stress factors and maternal-fetal adaptive response: the corticotropin-releasing factor family | journal = Endocrine | volume = 19 | issue = 1 | pages = 91–102 | year = 2003 | pmid = 12583606 | doi = 10.1385/ENDO:19:1:91 }}
  • {{cite journal |vauthors=Florio P, Rossi M, Sigurdardottir M, Ciarmela P, Luisi S, Viganò P, Grasso D, Fiore G, Cobellis L, Di Blasio AM, Petraglia F | title = Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A | journal = Steroids | volume = 68 | issue = 10–13 | pages = 801–7 | year = 2003 | pmid = 14667971 | doi = 10.1016/S0039-128X(03)00137-5 }}
  • {{cite journal |vauthors=Vamvakopoulos NC, Karl M, Mayol V, Gomez T, Stratakis CA, Margioris A, Chrousos GP | title = Structural analysis of the regulatory region of the human corticotropin releasing hormone gene | journal = FEBS Lett. | volume = 267 | issue = 1 | pages = 1–5 | year = 1990 | pmid = 2365075 | doi = 10.1016/0014-5793(90)80272-K }}
  • {{cite journal |vauthors=Robinson BG, D'Angio LA, Pasieka KB, Majzoub JA | title = Preprocorticotropin releasing hormone: cDNA sequence and in vitro processing | journal = Mol. Cell. Endocrinol. | volume = 61 | issue = 2 | pages = 175–80 | year = 1989 | pmid = 2783917 | doi = 10.1016/0303-7207(89)90128-7 }}
  • {{cite journal |vauthors=Arbiser JL, Morton CC, Bruns GA, Majzoub JA | title = Human corticotropin releasing hormone gene is located on the long arm of chromosome 8 | journal = Cytogenet. Cell Genet. | volume = 47 | issue = 3 | pages = 113–6 | year = 1988 | pmid = 3259914 | doi = 10.1159/000132525 }}
  • {{cite journal |vauthors=Sasaki A, Tempst P, Liotta AS, Margioris AN, Hood LE, Kent SB, Sato S, Shinkawa O, Yoshinaga K, Krieger DT | title = Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta | journal = J. Clin. Endocrinol. Metab. | volume = 67 | issue = 4 | pages = 768–73 | year = 1988 | pmid = 3262120 | doi = 10.1210/jcem-67-4-768 }}
  • {{cite journal |vauthors=Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, Horikawa S, Numa S | title = Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene | journal = EMBO J. | volume = 2 | issue = 5 | pages = 775–9 | year = 1984 | pmid = 6605851 | pmc = 555184 | doi = 10.1002/j.1460-2075.1983.tb01499.x}}
  • {{cite journal |vauthors=Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N, De Souza EB | title = Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease | journal = Nature | volume = 378 | issue = 6554 | pages = 284–7 | year = 1995 | pmid = 7477348 | doi = 10.1038/378284a0 |bibcode = 1995Natur.378..284B }}
  • {{cite journal |vauthors=Kawahito Y, Sano H, Mukai S, Asai K, Kimura S, Yamamura Y, Kato H, Chrousos GP, Wilder RL, Kondo M | title = Corticotropin releasing hormone in colonic mucosa in patients with ulcerative colitis | journal = Gut | volume = 37 | issue = 4 | pages = 544–51 | year = 1996 | pmid = 7489943 | pmc = 1382908 | doi = 10.1136/gut.37.4.544 }}
  • {{cite journal |vauthors=McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R | title = A placental clock controlling the length of human pregnancy | journal = Nat. Med. | volume = 1 | issue = 5 | pages = 460–3 | year = 1995 | pmid = 7585095 | doi = 10.1038/nm0595-460 }}
  • {{cite journal |vauthors=Slominski A, Ermak G, Hwang J, Chakraborty A, Mazurkiewicz JE, Mihm M | title = Proopiomelanocortin, corticotropin releasing hormone and corticotropin releasing hormone receptor genes are expressed in human skin | journal = FEBS Lett. | volume = 374 | issue = 1 | pages = 113–6 | year = 1995 | pmid = 7589495 | doi = 10.1016/0014-5793(95)01090-2 }}
  • {{cite journal |vauthors=Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, Potter E, Perrin MH, Rivier J, Vale WW | title = Ligand requirements of the human corticotropin-releasing factor-binding protein | journal = Endocrinology | volume = 136 | issue = 3 | pages = 1097–102 | year = 1995 | pmid = 7867564 | doi = 10.1210/en.136.3.1097 }}
  • {{cite journal |vauthors=Vamvakopoulos NC, Chrousos GP | title = Structural organization of the 5' flanking region of the human corticotropin releasing hormone gene | journal = DNA Seq. | volume = 4 | issue = 3 | pages = 197–206 | year = 1994 | pmid = 8161822 | doi = 10.3109/10425179309015632 }}
  • {{cite journal |vauthors=Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW | title = Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor | journal = Endocrinology | volume = 133 | issue = 6 | pages = 3058–61 | year = 1994 | pmid = 8243338 | doi = 10.1210/en.133.6.3058 }}
  • {{cite journal |vauthors=Romier C, Bernassau JM, Cambillau C, Darbon H | title = Solution structure of human corticotropin releasing factor by 1H NMR and distance geometry with restrained molecular dynamics | journal = Protein Eng. | volume = 6 | issue = 2 | pages = 149–56 | year = 1993 | pmid = 8386360 | doi = 10.1093/protein/6.2.149 }}
  • {{cite journal |vauthors=Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA | title = Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach | journal = Mol. Endocrinol. | volume = 11 | issue = 7 | pages = 980–5 | year = 1997 | pmid = 9178757 | doi = 10.1210/me.11.7.980 }}
  • {{cite journal |vauthors=Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W | title = Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1 | journal = Nat. Genet. | volume = 19 | issue = 2 | pages = 162–6 | year = 1998 | pmid = 9620773 | doi = 10.1038/520 }}
  • {{cite journal |vauthors=Perone MJ, Murray CA, Brown OA, Gibson S, White A, Linton EA, Perkins AV, Lowenstein PR, Castro MG | title = Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells | journal = Mol. Cell. Endocrinol. | volume = 142 | issue = 1–2 | pages = 191–202 | year = 1998 | pmid = 9783915 | doi = 10.1016/S0303-7207(98)00104-X }}
  • {{cite journal |vauthors=Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, Chrousos GP | title = Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function | journal = Mol. Psychiatry | volume = 5 | issue = 2 | pages = 137–41 | year = 2000 | pmid = 10822340 | doi = 10.1038/sj.mp.4000720 }}
  • {{cite journal |vauthors=Saeed B, Fawcett M, Self C | title = Corticotropin-releasing hormone binding to the syncytiotrophoblast membranes | journal = Eur. J. Clin. Invest. | volume = 31 | issue = 2 | pages = 125–30 | year = 2001 | pmid = 11168450 | doi = 10.1046/j.1365-2362.2001.00770.x }}
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5 : Hormones of the hypothalamus|Peptide hormones|Corticotropin-releasing hormone|Corticotropin-releasing hormone receptor agonists|Hormones of the hypothalamus-pituitary-adrenal axis
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