Corticotropin-releasing hormone

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).

CRH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3EHU, 3EHT, 1GOE
Identifiers
Aliases	CRH, CRF, CRH1, corticotropin releasing hormone
External IDs	OMIM: 122560 MGI: 88496 HomoloGene: 599 GeneCards: CRH
Gene location (Human) Chr. Chromosome 8 (human)^[1] Band 8q13.1 Start 66,176,376 bp^[1] End 66,178,464 bp^[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)^[2] Band 3 A2|3 5.75 cM Start 19,747,565 bp^[2] End 19,749,560 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in placenta Brodmann area 46 prefrontal cortex Brodmann area 10 frontal pole cingulate gyrus orbitofrontal cortex dorsolateral prefrontal cortex hypothalamus endothelial cell Top expressed in medial vestibular nucleus olfactory tubercle central amygdaloid nucleus paraventricular nucleus of hypothalamus lateral hypothalamus medial geniculate nucleus nucleus accumbens dorsal tegmental nucleus piriform cortex prefrontal cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hormone activity corticotropin-releasing hormone receptor 1 binding corticotropin-releasing hormone receptor 2 binding protein binding neuropeptide hormone activity signaling receptor binding corticotropin-releasing hormone activity Cellular component cytoplasm perikaryon varicosity extracellular region neuronal cell body extracellular space Biological process response to cocaine response to immobilization stress positive regulation of cortisol secretion steroid metabolic process positive regulation of protein phosphorylation negative regulation of luteinizing hormone secretion positive regulation of cell death associative learning ion homeostasis lung development diterpenoid metabolic process response to corticosterone female pregnancy negative regulation of norepinephrine secretion adrenal gland development synaptic transmission, dopaminergic negative regulation of cell death negative regulation of gene expression cellular response to dexamethasone stimulus positive regulation of corticosterone secretion response to estrogen locomotory exploration behavior regulation of NMDA receptor activity regulation of serotonin secretion positive regulation of calcium ion import glucocorticoid biosynthetic process positive regulation of gene expression positive regulation of digestive system process birth response to pain positive regulation of circadian sleep/wake cycle, wakefulness positive regulation of cell population proliferation hypothalamus development learning or memory hormone-mediated apoptotic signaling pathway positive regulation of insulin secretion involved in cellular response to glucose stimulus response to ethanol inflammatory response negative regulation of circadian sleep/wake cycle, REM sleep response to ether positive regulation of behavioral fear response signal transduction cellular response to cocaine long-term potentiation chemical synaptic transmission negative regulation of epinephrine secretion negative regulation of glucagon secretion G protein-coupled receptor signaling pathway negative regulation of systemic arterial blood pressure positive regulation of cAMP-mediated signaling positive regulation of corticotropin secretion Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 3: 19.75 – 19.75 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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

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

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

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

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

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

References

1. GRCh38: Ensembl release 89: ENSG00000147571 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000049796 - Ensembl, May 2017
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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.
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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.
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Further reading

• Florio P, Severi FM, Ciarmela P, Fiore G, Calonaci G, Merola A, et al. (October 2002). "Placental stress factors and maternal-fetal adaptive response: the corticotropin-releasing factor family". Endocrine. 19 (1): 91–102. doi:10.1385/ENDO:19:1:91. PMID 12583606. S2CID 39099605.
• Florio P, Rossi M, Sigurdardottir M, Ciarmela P, Luisi S, Viganò P, et al. (November 2003). "Paracrine regulation of endometrial function: interaction between progesterone and corticotropin-releasing factor (CRF) and activin A". Steroids. 68 (10–13): 801–807. doi:10.1016/S0039-128X(03)00137-5. PMID 14667971. S2CID 20953018.
• Vamvakopoulos NC, Karl M, Mayol V, Gomez T, Stratakis CA, Margioris A, et al. (July 1990). "Structural analysis of the regulatory region of the human corticotropin releasing hormone gene". FEBS Letters. 267 (1): 1–5. doi:10.1016/0014-5793(90)80272-K. PMID 2365075. S2CID 27597930.
• Robinson BG, D'Angio LA, Pasieka KB, Majzoub JA (February 1989). "Preprocorticotropin releasing hormone: cDNA sequence and in vitro processing". Molecular and Cellular Endocrinology. 61 (2): 175–180. doi:10.1016/0303-7207(89)90128-7. PMID 2783917. S2CID 31350703.
• Arbiser JL, Morton CC, Bruns GA, Majzoub JA (1988). "Human corticotropin releasing hormone gene is located on the long arm of chromosome 8". Cytogenetics and Cell Genetics. 47 (3): 113–116. doi:10.1159/000132525. PMID 3259914.
• Sasaki A, Tempst P, Liotta AS, Margioris AN, Hood LE, Kent SB, et al. (October 1988). "Isolation and characterization of a corticotropin-releasing hormone-like peptide from human placenta". The Journal of Clinical Endocrinology and Metabolism. 67 (4): 768–773. doi:10.1210/jcem-67-4-768. PMID 3262120.
• Shibahara S, Morimoto Y, Furutani Y, Notake M, Takahashi H, Shimizu S, et al. (1984). "Isolation and sequence analysis of the human corticotropin-releasing factor precursor gene". The EMBO Journal. 2 (5): 775–779. doi:10.1002/j.1460-2075.1983.tb01499.x. PMC 555184. PMID 6605851.
• Behan DP, Heinrichs SC, Troncoso JC, Liu XJ, Kawas CH, Ling N, et al. (November 1995). "Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease". Nature. 378 (6554): 284–287. Bibcode:1995Natur.378..284B. doi:10.1038/378284a0. PMID 7477348. S2CID 4305815.
• Kawahito Y, Sano H, Mukai S, Asai K, Kimura S, Yamamura Y, et al. (October 1995). "Corticotropin releasing hormone in colonic mucosa in patients with ulcerative colitis". Gut. 37 (4): 544–551. doi:10.1136/gut.37.4.544. PMC 1382908. PMID 7489943.
• McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R (May 1995). "A placental clock controlling the length of human pregnancy". Nature Medicine. 1 (5): 460–463. doi:10.1038/nm0595-460. PMID 7585095. S2CID 27897688.
• Slominski A, Ermak G, Hwang J, Chakraborty A, Mazurkiewicz JE, Mihm M (October 1995). "Proopiomelanocortin, corticotropin releasing hormone and corticotropin releasing hormone receptor genes are expressed in human skin". FEBS Letters. 374 (1): 113–116. doi:10.1016/0014-5793(95)01090-2. PMID 7589495. S2CID 37397132.
• Sutton SW, Behan DP, Lahrichi SL, Kaiser R, Corrigan A, Lowry P, et al. (March 1995). "Ligand requirements of the human corticotropin-releasing factor-binding protein". Endocrinology. 136 (3): 1097–1102. doi:10.1210/endo.136.3.7867564. PMID 7867564.
• Vamvakopoulos NC, Chrousos GP (1994). "Structural organization of the 5' flanking region of the human corticotropin releasing hormone gene". DNA Sequence. 4 (3): 197–206. doi:10.3109/10425179309015632. PMID 8161822.
• Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW (December 1993). "Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor". Endocrinology. 133 (6): 3058–3061. doi:10.1210/endo.133.6.8243338. PMID 8243338.
• Romier C, Bernassau JM, Cambillau C, Darbon H (February 1993). "Solution structure of human corticotropin releasing factor by 1H NMR and distance geometry with restrained molecular dynamics". Protein Engineering. 6 (2): 149–156. doi:10.1093/protein/6.2.149. PMID 8386360.
• Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA (June 1997). "Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach". Molecular Endocrinology. 11 (7): 980–985. doi:10.1210/mend.11.7.9946. PMID 9178757.
• Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, et al. (June 1998). "Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1". Nature Genetics. 19 (2): 162–166. doi:10.1038/520. PMID 9620773. S2CID 20336316.
• Perone MJ, Murray CA, Brown OA, Gibson S, White A, Linton EA, et al. (July 1998). "Procorticotrophin-releasing hormone: endoproteolytic processing and differential release of its derived peptides within AtT20 cells". Molecular and Cellular Endocrinology. 142 (1–2): 191–202. doi:10.1016/S0303-7207(98)00104-X. PMID 9783915. S2CID 10621100.
• Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, et al. (March 2000). "Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function". Molecular Psychiatry. 5 (2): 137–141. doi:10.1038/sj.mp.4000720. PMID 10822340.
• Saeed B, Fawcett M, Self C (February 2001). "Corticotropin-releasing hormone binding to the syncytiotrophoblast membranes". European Journal of Clinical Investigation. 31 (2): 125–130. doi:10.1046/j.1365-2362.2001.00770.x. PMID 11168450. S2CID 42612842.

External links

•   Media related to Corticotropin releasing hormone at Wikimedia Commons
• Overview of all the structural information available in the PDB for UniProt: P06850 (Corticoliberin) at the PDBe-KB.