Growth hormone releasing hormone (GHRH), also known as growth hormone or several other names of its endogenous form, as well as its drug form of growth hormone (INN), is a growth hormone (GH) releasing hormone.It is a peptide hormone of 44 amino acids produced in the hypothalamic arcuate nucleus.
GHRH first appears in the human hypothalamus between 18 and 29 weeks of gestation, which corresponds to the production of growth hormones and other growth hormones in the fetus.
GHRH is released from the nerve secretory nerve endings of these arcuate neurons and carried to the anterior pituitary by the hypothalamic-pituitary portal system. GHRH stimulates the secretion of growth hormone (GH) by stimulating the growth hormone releasing hormone receptor.GHRH is released in the form of pulse, which stimulates the similar release of GH.In addition, GHRH also directly promotes slow wave sleep.Growth hormone is required for normal postnatal growth, bone growth, and regulation of protein, carbohydrate, and lipid metabolism.
GHRH stimulates GH production and release by binding to the GHRH receptor (GHRHR) on the anterior pituitary cells.
The binding of GHRH and GHRHR is mainly through the camp-dependent pathway, but also through the phospholipase C pathway (IP3 / DAG pathway) and other secondary pathways to increase GH production.
The cAMP-dependent pathway is triggered by the binding of GHRH to its receptor, causing the conformation of the receptor, which activates Gs subunits of the tightly bound G protein complex inside the cell.This results in the stimulation of membrane-bound adenylate cyclase and the increase of intracellular cyclic adenosine monophosphate (cAMP).CAMP binds and activates the regulatory subunit of protein kinase A (PKA), allowing free catalytic subunit translocation to the nucleus and phosphorylation of the transcription factor cAMP responsive element binding protein (CREB).Phosphorylation of CREB and its co-activators, p300 and CREB binding protein (CBP), enhances GH transcription by binding the CREs cAMP response element in the GH gene promoter region.It can also increase the transcription of GHRHR gene and provide positive feedback.
In the phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through a complex of heterotrimeric G protein.Activation by PLC produces diacylglycerin (DAG) and inositol triphosphate (IP3), which results in intracellular Ca2 + release from the endoplasmic reticulum and increases the concentration of cellular solute Ca2 +, leading to vesicle fusion and the release of secreted vesicles containing prefabricated growth hormones.
Some Ca2 + influx is also A direct effect of cAMP, which is different from the usual camp-dependent activation of protein kinase A pathway.
GHRH activation of GHRHR also leads to cell depolarization through the opening of phosphatidylinositol 4, 5-diphosphate transfer Na + channel.The resulting intracellular voltage change opens the voltage-dependent calcium channel, leading to vesicular fusion and GH release.
The relationship between GHRH and somatostatin
Somatostatin (growth hormone inhibitory hormone) opposes the role of GHRH.Somatostatin is released from the neurosecretory nerve endings of somatostatin neurons around the ventricle and carried by the hypothalamic-pituitary portal circulation to the anterior pituitary, where GH secretion is inhibited.Somatostatin and GHRH were secreted alternately, which caused significant pulsating secretion of GH.
GHRH expression has been confirmed in peripheral cells and tissues outside the main parts of the hypothalamus, for example, in the pancreas, gastrointestinal epithelial mucosa and pathology, and in tumor cells.
The amino acid sequence (44 length) of human GHRH is:
HO – Tyr – Ala – Asp – Ala – Ile – Phe – Thr – Asn – Ser – Tyr – Arg – Lys – Val – Leu – Gln – glu – Ser – Ala – Arg – Leu – Leu – Gln -Asp – Ile – Met – Ser – Arg – Gln – Gln – Glu – Ser – Asn – Gln – Glu – Arg – Glu – Ala – Ala – Arg – Leu – NH2
Growth hormone releasing hormone is the main compound of many structural and functional analogues, such as pro-pro-hghrh (1-44) -gly-gly-cys, cjc-1293 and cjc-1295.
Many GHRH analogues are still primarily chemicals, although some have specific applications.Sermorelin is a functional peptide fragment of GHRH and has been used to diagnose defects in growth hormone secretion.Tesamorelin, under the trade name Egrifta, was approved by the us food and drug administration in 2010 to treat fat metabolism disorders in HIV patients receiving highly active antiretroviral therapy. In 2011, Tesamorelin investigated the impact of certain cognitive tests on the elderly.As a category, the use of GHRH analogues by professional athletes may be restricted to sports because they can be used as growth hormone secretion enhancers.
GHRH peptide analogues: cjc-1295, Mod GRF, Sermorelin
Cjc-1295 – also known as CJC1295 DAC and mpa-lys30, d-ala2, Gln8, Ala15, leu27-grf amide:
Cjc-1295 DAC, a 4-substituted analog of GRF 1-29, has d-ala at 2-, Gln at 8- to reduce asparagine rearrangement or amide hydrolysis to aspartic acid, and Leu at 15 -Ala to enhance biological activity and position 27 to prevent protein oxidation and c-terminal mpa-lys.Cjc-1295, a maleimide derivative of GRF 1-29, is modified in such a way that it has the ability to bioconjugate with serum albumin, thereby increasing its half-life and possible therapeutic window.
Modified GRF 1-29 – also known as d-ala2, Gln8, Ala15, leu27-grf amide:
Modified GRF 1-29 is a 4-substituted analogue of GRF 1-29, which has d-ala at 2-position and Gln at 8-position to reduce asparagine rearrangement or amide hydrolysis to aspartic acid, and Ala at 15 position.Enhance bioactivity and provide Leu at 27 sites to prevent methionine oxidation.Mod GRF 1-29 is modified in such a way as to increase its half-life and possible therapeutic window, but in a more natural pulsating manner similar to GRF 1-44.
Sermorelin – also known as GRF 1-29 and GRF 1-29 amide:
Sermorelin is a growth hormone releasing hormone analogue. It is a polypeptide of 29- amino acid, representing 1-29 fragments from the endogenous human growth hormone releasing hormone, and is considered as the shortest complete functional fragment of GHRH.