Corticotropin-releasing hormone

Last updated

CRH
PBB Protein CRH image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CRH , CRF, CRH1, corticotropin releasing hormone
External IDs OMIM: 122560 MGI: 88496 HomoloGene: 599 GeneCards: CRH
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 Mb Chr 3: 19.75 – 19.75 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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).

Contents

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]

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:

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

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

Related Research Articles

<span class="mw-page-title-main">Adrenocorticotropic hormone</span> Pituitary hormone

Adrenocorticotropic hormone is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production and release of cortisol and androgens by the cortex and medulla of the adrenal gland, respectively. ACTH is also related to the circadian rhythm in many organisms.

<span class="mw-page-title-main">Hypothalamus</span> Area of the brain below the thalamus

The hypothalamus is a small part of the brain that contains a number of nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. It forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.

<span class="mw-page-title-main">Thyrotropin-releasing hormone</span> Hormone

Thyrotropin-releasing hormone (TRH) is a hypophysiotropic hormone produced by neurons in the hypothalamus that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPA axis.

Corticotropin-releasing factor family, CRF family is a family of related neuropeptides in vertebrates. This family includes corticotropin-releasing hormone, urotensin-I, urocortin, and sauvagine. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRH forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as prohormones.

<span class="mw-page-title-main">Paraventricular nucleus of hypothalamus</span>

The paraventricular nucleus is a nucleus in the hypothalamus. Anatomically, it is adjacent to the third ventricle and many of its neurons project to the posterior pituitary. These projecting neurons secrete oxytocin and a smaller amount of vasopressin, otherwise the nucleus also secretes corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH). CRH and TRH are secreted into the hypophyseal portal system and act on different targets neurons in the anterior pituitary. PVN is thought to mediate many diverse functions through these different hormones, including osmoregulation, appetite, and the response of the body to stress.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Neuropeptide Y</span> Mammalian protein found in Homo sapiens

Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glutamate. 

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

<span class="mw-page-title-main">Urocortin</span>

Urocortin is a protein that in humans is encoded by the UCN gene. Urocortin belongs to the corticotropin-releasing factor (CRF) family of proteins which includes CRF, urotensin I, sauvagine, urocortin II and urocortin III. Urocortin is involved in the mammalian stress response, and regulates aspects of appetite and stress response.

Urocortin III, a 38–41 amino acid peptide, is a member of the CRF, also known as CRH family of peptides, with a long evolutionary lineage.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 1</span> Protein and coding gene in humans

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name. In humans, CRF1 is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.

<span class="mw-page-title-main">Corticotropin-releasing hormone receptor 2</span> Protein found in humans

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.

<span class="mw-page-title-main">CRHBP</span> Protein-coding gene in the species Homo sapiens

Corticotropin-releasing factor-binding protein is a protein that in humans is encoded by the CRHBP gene. It belongs to corticotropin-releasing hormone binding protein family.

<span class="mw-page-title-main">Antalarmin</span> Chemical compound

Antalarmin (CP-156,181) is a drug that acts as a CRH1 antagonist.

A Corticotropin-releasing hormone antagonist is a specific type of receptor antagonist that blocks the receptor sites for corticotropin-releasing hormone, also known as corticotropin-releasing factor (CRF), which synchronizes the behavioral, endocrine, autonomic, and immune responses to stress by controlling the hypothalamic-pituitary-adrenal axis. CRH antagonists thereby block the consequent secretions of ACTH and cortisol due to stress, among other effects.

Parvocellular neurosecretory cells are small neurons that produce hypothalamic releasing and inhibiting hormones. The cell bodies of these neurons are located in various nuclei of the hypothalamus or in closely related areas of the basal brain, mainly in the medial zone of the hypothalamus. All or most of the axons of the parvocellular neurosecretory cells project to the median eminence, at the base of the brain, where their nerve terminals release the hypothalamic hormones. These hormones are then immediately absorbed into the blood vessels of the hypothalamo-pituitary portal system, which carry them to the anterior pituitary gland, where they regulate the secretion of hormones into the systemic circulation.

Corticotropin-releasing hormone binding protein (CRH-BP) binds corticotropin-releasing hormone (CRH) and several related peptide hormones. It is an ancient, highly conserved protein whose origin predates the divergence of protostomes and deuterostomes.

Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000147571 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 "Entrez Gene: CRH corticotropin releasing hormone".
  6. 1 2 3 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. ISSN   0362-1642. 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