Growth hormone–releasing hormone

Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by several other names in its endogenous forms 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.

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

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

• 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

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

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

Receptor

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

Signal transduction

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 G_s 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

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-hypophysial 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.

Other functions

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

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

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,[6] CJC-1293,[7] and CJC-1295.[8]

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.[9] Tesamorelin,[10] 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,[11] and, in 2011, was investigated for effects on certain cognitive tests in the elderly.[12] 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.[13]

See also

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

References

1. GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009
2. Plotsky, PM; Vale, W (25 October 1985). "Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat". Science. 230 (4724): 461–3. Bibcode:1985Sci...230..461P. doi:10.1126/science.2864742. PMID 2864742.
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.
4. Obál F, Krueger J (2001). "The somatotropic axis and sleep". Rev Neurol (Paris). 157 (11 Pt 2): S12–5. PMID 11924022.
5. Walter F. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
6. Tang SS, Zhang JH, Du MH, Wu J, Liu JJ (2004). "Construction and activity of a novel GHRH analog, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys". Acta Pharmacol. Sin. 25 (11): 1464–70. PMID 15525469.
7. Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP (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): 3052–8. doi:10.1210/en.2004-1286. PMID 15817669.
8. Teichman, SL; et al. (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" (PDF). J Clin Endocrinol Metab. 91 (3): 799–805. doi:10.1210/jc.2005-1536. PMID 16352683.
9. 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): 139–57. doi:10.2165/00063030-199912020-00007. PMID 18031173.
10. Mauss, Stefan; Schmutz, Günther (2001). "Das HIV-assoziierte Lipodystrophiesyndrom". Medizinische Klinik. 96 (7): 391–401. doi:10.1007/PL00002220. PMID 11494914.
11. "FDA approves Egrifta to treat Lipodystrophy in HIV patients". U.S. Food and Drug Administration. 2010-11-10. Retrieved 2013-09-13.
12. Gever, John (2011-07-11). "ICAD: Tesamorelin Boosts Cognition in Elderly". MedPage Today. Retrieved 2013-09-13.
13. Koh, Benjamin; Hardie, Martin (2013-02-11). "We need an advocate against ASADA's power in doping control". The Conversation. Retrieved 2013-09-13.