| 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. 20p12 or q11.2-q12 | ||||||
| |||||||
Growth hormone–releasing hormone (GHRH), also known assomatocrinin among other names in itsendogenous form and assomatorelin (INN) in itspharmaceutical form, is areleasing hormone ofgrowth hormone (GH). It is a 44[1]-amino acidpeptide hormone produced in thearcuate nucleus of thehypothalamus.
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]
GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophyseal portal system to theanterior pituitary gland, where it stimulatesgrowth hormone (GH) secretion by stimulating thegrowth hormone-releasing hormone receptor. GHRH is released in a pulsatile manner,[2][3] stimulating similar pulsatile release of GH. In addition, GHRH also promotesslow-wave sleep directly.[4] Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.[1]
GHRH stimulates GH production and release by binding to the GHRH receptor (GHRHR) on cells in the anterior pituitary.
The GHRHR is a member of thesecretin family ofG protein-coupled receptors, and is located onchromosome 7 in humans. This protein is transmembranous with seven folds, and its molecular weight is approximately 44kD.[1]
GHRH binding to GHRHR results in increased GH production mainly by thecAMP-dependent pathway,[5] but also by thephospholipase C pathway (IP3/DAG pathway),[1] and other minor pathways.[1]
ThecAMP-dependent pathway is initiated by the binding of GHRH to its receptor, causing receptor conformation that activatesGs alpha subunit of the closely associated G-Protein complex on the intracellular side. This results in stimulation of membrane-boundadenylyl cyclase and increased intracellularcyclic adenosine monophosphate (cAMP). cAMP binds to and activates the regulatory subunits ofprotein kinase A (PKA), allowing the free catalytic subunits to translocate to the nucleus and phosphorylate the transcription factorcAMP response element-binding protein (CREB). Phosphorylated CREB, together with its coactivators,p300 andCREB-binding protein (CBP) enhances the transcription of GH by binding to CREscAMP-response elements in thepromoter region of the GH gene. It also increases transcription of the GHRHR gene, providingpositive feedback.[1]
In thephospholipase C pathway, GHRH stimulates phospholipase C (PLC) through theβγ-complex ofheterotrimeric G-proteins. PLC activation produces bothdiacylglycerol (DAG) andinositol triphosphate (IP3), the latter leading to release of intracellular Ca2+ from theendoplasmic reticulum, increasing cytosolic Ca2+ concentration, resulting invesicle 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 usualcAMP-dependent pathway of activatingprotein kinase A.[1]
Activation of GHRHRs by GHRH also conveys opening ofNa+ channels byphosphatidylinositol 4,5-bisphosphate, causing cell depolarization. The resultant change in the intracellular voltage opens avoltage-dependent calcium channel, resulting invesicle fusion and release of GH.[1]
The actions of GHRH are opposed bysomatostatin (growth-hormone-inhibiting hormone). Somatostatin is released from neurosecretory nerve terminals of periventricular somatostatin neurons, and is carried by thehypothalamo-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]
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]
Theamino 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
Growth-hormone-releasing hormone is thelead compound for a number ofstructural andfunctional analogs, such as Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys,[7] CJC-1293,[8] andCJC-1295.[9]
Many GHRH analogs remain primarilyresearch chemicals, although some have specific applications.Sermorelin, a functionalpeptide 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 oflipodystrophy inHIV patients underhighly 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 ondoping in sport because they act as growth hormonesecretagogues.[14]