Growth hormone–releasing hormone

Mammalian protein found in Homo sapiens

Growth hormone releasing hormone

Identifiers
Symbol| GHRH
Alt. symbols| GRF, GHRF
CAS number| 9034-39-3
NCBI gene| 2691
HGNC| 4265
OMIM| 139190
RefSeq| NM_021081
UniProt| P01286
Other data
Locus| Chr. 20 p12 or q11.2-q12
| Search for

Structures| Swiss-model
Domains| InterPro

Growth hormone–releasing hormone (GHRH), also known as somatocrinin among other names in its endogenous form and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44[1]-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

GHRH first appears in the human hypothalamus between 18 and 29 weeks of gestation, which corresponds to the start of production of growth hormone and other somatotropes in fetuses.[1]

## Nomenclature

[edit]

* Endogenous:
* somatocrinin
* somatoliberin
* growth hormone–releasing hormone (GHRH or GH-RH; HGNC symbol is GHRH)
* growth hormone–releasing factor (GHRF or GRF)
* somatotropin-releasing hormone (SRH)
* somatotropin-releasing factor (SRF)
* Pharmaceutical:
* somatorelin (INN)

## Origin

[edit]

GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophyseal portal system to the anterior pituitary gland, where it stimulates growth hormone (GH) secretion by stimulating the growth hormone-releasing hormone receptor. GHRH is released in a pulsatile manner,[2][3] stimulating similar pulsatile release of GH. In addition, GHRH also promotes slow-wave sleep directly.[4] Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.[1]

## Effect

[edit]

GHRH stimulates GH production and release by binding to the GHRH receptor (GHRHR) on cells in the anterior pituitary.

### Receptor

[edit]

Main article: Growth hormone-releasing hormone receptor

The GHRHR is a member of the secretin family of G protein-coupled receptors, and is located on chromosome 7 in humans. This protein is transmembranous with seven folds, and its molecular weight is approximately 44 kD.[1]

### Signal transduction

[edit]

GHRH binding to GHRHR results in increased GH production mainly by the cAMP-dependent pathway,[5] but also by the phospholipase C pathway (IP3/DAG pathway),[1] and other minor pathways.[1]

The cAMP-dependent pathway is initiated by the binding of GHRH to its receptor, causing receptor conformation that activates Gs alpha subunit of the closely associated G-Protein complex on the intracellular side. This results in stimulation of membrane-bound adenylyl cyclase and increased intracellular cyclic adenosine monophosphate (cAMP). cAMP binds to and activates the regulatory subunits of protein kinase A (PKA), allowing the free catalytic subunits to translocate to the nucleus and phosphorylate the transcription factor cAMP response element-binding protein (CREB). Phosphorylated CREB, together with its coactivators, p300 and CREB-binding protein (CBP) enhances the transcription of GH by binding to CREs cAMP-response elements in the promoter region of the GH gene. It also increases transcription of the GHRHR gene, providing positive feedback.[1]

In the phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through the βγ-complex of heterotrimeric G-proteins. PLC activation produces both diacylglycerol (DAG) and inositol triphosphate (IP3), the latter leading to release of intracellular Ca2+ from the endoplasmic reticulum, increasing cytosolic Ca2+ concentration, resulting in vesicle fusion and release of secretory vesicles containing premade growth hormone.[1]

Some Ca2+ influx is also a direct action of cAMP, which is distinct from the usual cAMP-dependent pathway of activating protein kinase A.[1]

Activation of GHRHRs by GHRH also conveys opening of Na+ channels by phosphatidylinositol 4,5-bisphosphate, causing cell depolarization. The resultant change in the intracellular voltage opens a voltage-dependent calcium channel, resulting in vesicle fusion and release of GH.[1]

## Relationship of GHRH and somatostatin

[edit]

The actions of GHRH are opposed by somatostatin (growth-hormone-inhibiting hormone). Somatostatin is released from neurosecretory nerve terminals of periventricular somatostatin neurons, and is carried by the hypothalamo-hypophyseal portal circulation to the anterior pituitary where it inhibits GH secretion. Somatostatin and GHRH are secreted in alternation, giving rise to the markedly pulsatile secretion of GH.[6]

## Other functions

[edit]

GHRH expression has been demonstrated in peripheral cells and tissues outside its main site in the hypothalamus, for example, in the pancreas, epithelial mucosa of the gastrointestinal tract and, pathologically, in tumour cells.[1]

## Sequence

[edit]

The amino acid sequence (44 long) of human GHRH is:

HO - Tyr - Ala - Asp - Ala - Ile - Phe - Thr - Asn - Ser - Tyr - Arg - Lys - Val - Leu - Gly - Gln - Leu - Ser - Ala - Arg - Lys - Leu - Leu - Gln - Asp - Ile - Met - Ser - Arg - Gln - Gln - Gly - Glu - Ser - Asn - Gln - Glu - Arg - Gly - Ala - Arg - Ala - Arg - Leu - NH2

## Analogs

[edit]

Growth-hormone-releasing hormone is the lead compound for a number of structural and functional analogs, such as Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys,[7] CJC-1293,[8] and CJC-1295.[9]

Many GHRH analogs remain primarily research chemicals, although some have specific applications. Sermorelin, a functional peptide fragment of GHRH, has been used in the diagnosis of deficiencies in growth hormone secretion.[10] Tesamorelin,[11] under the trade name Egrifta, received U.S. Food and Drug Administration approval in 2010 for the treatment of lipodystrophy in HIV patients under highly active antiretroviral therapy,[12] and, in 2011, was investigated for effects on certain cognitive tests in the elderly.[13] As a category, the use of GHRH analogs by professional athletes may be prohibited by restrictions on doping in sport because they act as growth hormone secretagogues.[14]

## See also

[edit]

* Growth hormone secretagogue
* Hypothalamic–pituitary–somatic axis
* List of growth hormone secretagogues

## References

[edit]

1. ^ a b c d e f g h i j k GeneGlobe -> GHRH Signaling Archived 2020-10-09 at the Wayback Machine Retrieved on October 5, 2020
2. ^ Plotsky PM, Vale W (October 1985). "Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat". Science. 230 (4724): 461–463\. Bibcode:1985Sci...230..461P. doi:10.1126/science.2864742. PMID 2864742.461-463&rft.date=1985-10&rft_id=info:pmid/2864742&rft_id=info:doi/10.1126/science.2864742&rft_id=info:bibcode/1985Sci...230..461P&rft.aulast=Plotsky&rft.aufirst=PM&rft.au=Vale,+W&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
3. ^ Frohman LA, Downs TR, Clarke IJ, Thomas GB (July 1990). "Measurement of growth hormone-releasing hormone and somatostatin in hypothalamic-portal plasma of unanesthetized sheep. Spontaneous secretion and response to insulin-induced hypoglycemia". The Journal of Clinical Investigation. 86 (1): 17–24\. doi:10.1172/jci114681. PMC 296684. PMID 1973173.17-24&rft.date=1990-07&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC296684#id-name=PMC&rft_id=info:pmid/1973173&rft_id=info:doi/10.1172/jci114681&rft.aulast=Frohman&rft.aufirst=LA&rft.au=Downs,+TR&rft.au=Clarke,+IJ&rft.au=Thomas,+GB&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC296684&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
4. ^ Obál F, Krueger JM (November 2001). "The somatotropic axis and sleep". Revue Neurologique. 157 (11 Pt 2): S12 – S15. PMID 11924022.S12+-+S15&rft.date=2001-11&rft_id=info:pmid/11924022&rft.aulast=Obál&rft.aufirst=F&rft.au=Krueger,+JM&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
5. ^ Boron WF (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300\. ISBN 1-4160-2328-3.
6. ^ Lee J, Kim K, Cho JH, Bae JY, O'Leary TP, Johnson JD, et al. (August 2020). "Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production". JCI Insight. 5 (16): e135412. doi:10.1172/jci.insight.135412. PMC 7455129. PMID 32644973.
7. ^ Tang SS, Zhang JH, Du MH, Wu J, Liu JJ (November 2004). "Construction and activity of a novel GHRH analog, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys". Acta Pharmacologica Sinica. 25 (11): 1464–1470\. PMID 15525469.1464-1470&rft.date=2004-11&rft_id=info:pmid/15525469&rft.aulast=Tang&rft.aufirst=SS&rft.au=Zhang,+JH&rft.au=Du,+MH&rft.au=Wu,+J&rft.au=Liu,+JJ&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
8. ^ Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, et al. (July 2005). "Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog". Endocrinology. 146 (7): 3052–3058\. doi:10.1210/en.2004-1286. PMID 15817669.3052-3058&rft.date=2005-07&rft_id=info:doi/10.1210/en.2004-1286&rft_id=info:pmid/15817669&rft.aulast=Jetté&rft.aufirst=L&rft.au=Léger,+R&rft.au=Thibaudeau,+K&rft.au=Benquet,+C&rft.au=Robitaille,+M&rft.au=Pellerin,+I&rft.au=Paradis,+V&rft.au=van+Wyk,+P&rft.au=Pham,+K&rft.au=Bridon,+DP&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
9. ^ Teichman SL, Neale A, Lawrence B, Gagnon C, Castaigne JP, Frohman LA (March 2006). "Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults". The Journal of Clinical Endocrinology and Metabolism. 91 (3): 799–805\. doi:10.1210/jc.2005-1536. PMID 16352683.799-805&rft.date=2006-03&rft_id=info:doi/10.1210/jc.2005-1536&rft_id=info:pmid/16352683&rft.aulast=Teichman&rft.aufirst=SL&rft.au=Neale,+A&rft.au=Lawrence,+B&rft.au=Gagnon,+C&rft.au=Castaigne,+JP&rft.au=Frohman,+LA&rft_id=https://doi.org/10.1210%2Fjc.2005-1536&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
10. ^ Prakash A, Goa KL (August 1999). "Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency". BioDrugs. 12 (2): 139–157\. doi:10.2165/00063030-199912020-00007. PMID 18031173. S2CID 195690081.139-157&rft.date=1999-08&rft_id=https://api.semanticscholar.org/CorpusID:195690081#id-name=S2CID&rft_id=info:pmid/18031173&rft_id=info:doi/10.2165/00063030-199912020-00007&rft.aulast=Prakash&rft.aufirst=A&rft.au=Goa,+KL&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
11. ^ Mauss S, Schmutz G (July 2001). "[HIV-lipodystrophy syndrome]". Medizinische Klinik. 96 (7): 391–401\. doi:10.1007/PL00002220. PMID 11494914. S2CID 27548912.391-401&rft.date=2001-07&rft_id=https://api.semanticscholar.org/CorpusID:27548912#id-name=S2CID&rft_id=info:pmid/11494914&rft_id=info:doi/10.1007/PL00002220&rft.aulast=Mauss&rft.aufirst=S&rft.au=Schmutz,+G&rfr_id=info:sid/en.wikipedia.org:Growth+hormone–releasing+hormone" class="Z3988">
12. ^ "FDA approves Egrifta to treat Lipodystrophy in HIV patients". U.S. Food and Drug Administration. 2010-11-10. Retrieved 2013-09-13.
13. ^ Gever J (2011-07-11). "ICAD: Tesamorelin Boosts Cognition in Elderly". MedPage Today. Retrieved 2013-09-13.
14. ^ Koh B, Hardie M (2013-02-11). "We need an advocate against ASADA's power in doping control". The Conversation. Retrieved 2013-09-13.

* v
* t
* e

Hormones

Endocrine
glands|

| Hypothalamic–
pituitary|

| Hypothalamus|

* GnRH
* TRH
* Dopamine
* CRH
* GHRH
* Somatostatin (GHIH)
* MCH

|

Posterior pituitary|

* Oxytocin
* Vasopressin

Anterior pituitary|

* FSH
* LH
* TSH
* Prolactin
* POMC
* CLIP
* ACTH
* MSH
* Endorphins
* Lipotropin
* GH

Adrenal axis|

* Adrenal cortex
* Aldosterone
* Cortisol
* Cortisone
* DHEA
* DHEA-S
* Androstenedione
* Adrenal medulla
* Adrenaline
* Norepinephrine

Thyroid|

* Thyroid hormones
* T3
* T4
* Calcitonin
* Thyroid axis

Parathyroid|

* PTH

Gonadal axis|

| Testis|

* Testosterone
* AMH
* Inhibin

|

Ovary|

* Estradiol
* Progesterone
* Activin
* Inhibin
* Relaxin
* GnSAF

Placenta|

* hCG
* HPL
* Estrogen
* Progesterone

Pancreas|

* Glucagon
* Insulin
* Amylin
* Somatostatin
* Pancreatic polypeptide

Pineal gland|

* Melatonin
* N,N-Dimethyltryptamine
* 5-Methoxy-N,N-dimethyltryptamine

Other|

| Thymus|

* Thymosins
* Thymosin α1
* Beta thymosins
* Thymopoietin
* Thymulin

|

Digestive system|

| Stomach|

* Gastrin
* Ghrelin

|

Duodenum|

* CCK
* GIP
* Secretin
* Motilin
* VIP

Ileum|

* Enteroglucagon
* Peptide YY
* GLP-1

Liver/other|

* Insulin-like growth factor
* IGF-1
* IGF-2

Adipose tissue|

* Leptin
* Adiponectin
* Resistin

Skeleton|

* Osteocalcin

Kidney|

* Renin
* EPO
* Calcitriol
* Prostaglandin

Heart|

* Natriuretic peptide
* ANP
* BNP

* v
* t
* e

Peptides: neuropeptides

Hormones|

see hormones

Opioid peptides|

| Dynorphins|

* Dynorphin A
* Dynorphin A1–8
* Dynorphin B
* Big dynorphin
* Leumorphin
* α-Neoendorphin
* β-Neoendorphin

|

Endomorphins|

* Endomorphin-1
* Endomorphin-2

Endorphins|

* α-Endorphin
* β-Endorphin
* γ-Endorphin

Enkephalins|

* Met-enkephalin
* Leu-enkephalin

Others|

* Adrenorphin
* Amidorphin
* Hemorphin
* Hemorphin-4
* Nociceptin
* Opiorphin
* Spinorphin
* Valorphin

Other
neuropeptides|

| Kinins|

Bradykinins
Tachykinins: mammal

* Substance P
* Neurokinin A
* Neurokinin B

amphibian

* Kassinin
* Physalaemin

|

Neuromedins|

* B
* N
* S
* U

Orexins|

* A
* B

Other|

* Angiotensin
* Bombesin
* Calcitonin gene-related peptide
* Carnosine
* Cocaine- and amphetamine-regulated transcript
* Delta-sleep-inducing peptide
* FMRFamide
* Galanin
* Galanin-like peptide
* Gastrin-releasing peptide
* Ghrelin
* Neuropeptide AF
* Neuropeptide FF
* Neuropeptide SF
* Neuropeptide VF
* Neuropeptide S
* Neuropeptide Y
* Neurophysins
* Neurotensin
* Pancreatic polypeptide
* Pituitary adenylate cyclase-activating peptide
* RVD-Hpα
* VGF

* v
* t
* e

GH/IGF-1 axis signaling modulators

(somatotropin)|

* Agonists: Albusomatropin
* Bovine somatotropin
* Efpegsomatropin
* Eftansomatropin alfa
* Growth hormone
* Human placental lactogen
* Lonapegsomatropin
* Placental growth hormone (growth hormone variant)
* Somagrebove
* Somapacitan
* Somatosalm
* Somatotropin
* Somatropin pegol
* Somatrem
* Sometribove
* Somatrogon (MOD-4023; hGH-CTP)
* Somavaratan
* Somavubove
* Somidobove

* Antagonists: G120K-hGH
* Pegvisomant

* Antisense oligonucleotides: Atesidorsen

* Binding proteins: GHBPTooltip Growth hormone-binding protein

GHIH
(somatostatin)|

* Agonists: BIM-23052
* CH-275
* Cortistatin-14
* Depreotide
* Edotreotide
* Ilatreotide
* L-803,087
* L-817,818
* Lanreotide
* NNC 26-9100
* Octreotate
* Octreotide
* Pasireotide
* Pentetreotide
* RC-160
* Seglitide
* Somatostatin (GHIH)
* Somatostatin (1-28)
* SRIF-14
* SRIF-28
* TT-232
* Vapreotide
* Veldoreotide

* Antagonists: BIM-23056
* Cyclosomatostatin
* CYN-154806
* Satoreotide

GHRH
(somatocrinin)|

* Agonists: Peptide: ALRN-5281
* CJC-1295
* Dumorelin
* GHRH
* Modified GRF (1-29)
* Rismorelin
* Sermorelin
* Somatorelin
* Tesamorelin

* Antagonists: MZ-5-156

GHS
(ghrelin)|

* Agonists: Peptide: Alexamorelin
* Cortistatin-14
* EP-51216
* Examorelin (hexarelin)
* Ghrelin
* GHRP-1
* GHRP-3
* GHRP-4
* GHRP-5
* GHRP-6
* Ipamorelin
* Lenomorelin
* Livoletide
* LY-444711
* Pralmorelin (GHRP-2)
* Relamorelin
* Tabimorelin
* Ulimorelin; Non-peptide: Adenosine
* Anamorelin
* Capromorelin
* CP-464709
* Ibutamoren (MK-677)
* L-692,585
* Macimorelin
* SM-130686; Unsorted: LY-426410
* LY-444711

* Antagonists: A-778193
* Cortistatin-8
* (D-Lys³)-GHRP-6
* JMV2959
* YIL-781

IGF-1
(somatomedin)|

* See here instead.

*[v]: View this template
*[t]: Discuss this template
*[e]: Edit this template
*[GH]: Growth hormone
*[IGF-1]: Insulin-like growth factor 1
*[GHBP]: Growth hormone-binding protein
*[GHIH]: Growth hormone-inhibiting hormone
*[GHRH]: Growth hormone releasing hormone
*[GHS]: Growth hormone secretagogue