Growth hormone releasing hormone
Encyclopedia
Growth-hormone-releasing hormone (GHRH), also known as growth-hormone-releasing factor (GRF, GHRF), somatoliberin or somatocrinin, is a releasing hormone
for growth hormone
. It is a 44-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.
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, stimulating similar pulsatile release of GH. In addition, GHRH also promotes slow-wave sleep
directly. Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.
s, and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is approximately 44 kD.
, but also by the phospholipase C pathway (IP3/DAG pathway), and other minor pathways.
The cAMP-dependent pathway is initiated by GHRH binding 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
.
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.
Some Ca2+ influx is also a direct action of cAMP, which is distinct from the usual cAMP dependent pathway of activating protein kinase A.
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.
(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.
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
in HIV
patients under highly active antiretroviral therapy, approved by the U.S. Food and Drug Administration
in November 2010. Chemically it is (3E)-hex-3-enoyl-GHRH. It may also reduce cognitive decline in older humans.
See also earlier work on Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys. CJC-1295
, CJC-1293
and Sermorelin
.
Releasing hormone
A releasing hormone or releasing factor is a hormone whose main purpose is to control the release of another hormone. The main releasing hormones secreted by the hypothalamus are:*Thyrotropin-releasing hormone ,...
for growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
. It is a 44-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide hormone
Peptide hormone
Peptide hormones are a class of peptides that are secreted into the blood stream and have endocrine functions in living animals.Like other proteins, peptide hormones are synthesized in cells from amino acids according to an mRNA template, which is itself synthesized from a DNA template inside the...
produced in the arcuate nucleus
Arcuate nucleus
The arcuate nucleus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence...
of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
.
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.
Origin
GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophyseal portal systemHypophyseal portal system
The hypophyseal portal system is the system of blood vessels that link the hypothalamus and the anterior pituitary in the brain.It allows endocrine communication between the two structures. It is part of the hypothalamic-pituitary-adrenal axis. The anterior pituitary receives releasing and...
to the anterior pituitary gland where it stimulates growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
(GH) secretion by stimulating the growth hormone-releasing hormone receptor. GHRH is released in a pulsatile manner, stimulating similar pulsatile release of GH. In addition, GHRH also promotes slow-wave sleep
Slow-wave sleep
Slow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...
directly. Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.
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 receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s, and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is approximately 44 kD.
Signal transduction
GHRH binding to GHRHR results in increased GH production mainly by the cAMP dependent pathwayCAMP dependent pathway
In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.-Mechanism:...
, but also by the phospholipase C pathway (IP3/DAG pathway), and other minor pathways.
The cAMP-dependent pathway is initiated by GHRH binding to its receptor, causing receptor conformation that activates Gs alpha subunit
Gs alpha subunit
The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:...
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
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(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
P300
The P300 wave is an event related potential elicited by infrequent, task-relevant stimuli. It is considered to be an endogenous potential as its occurrence links not to the physical attributes of a stimulus but to a person's reaction to the stimulus. More specifically, the P300 is thought to...
and CREB binding protein
CREB binding protein
CREB-binding protein, also known as CREBBP or CBP, is a protein that in humans is encoded by the CREBBP gene.The CREB protein carries out its function by activating transcription, where interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor...
(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
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
.
In the phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through the βγ-complex of heterotrimeric G-proteins. PLC activation produces both diacylglycerol
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
(DAG) and inositol triphosphate
Inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell...
(IP3), the latter leading to release of intracellular Ca2+ from the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, increasing cytosolic Ca2+ concentration, resulting in vesicle fusion
Vesicle fusion
Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis at the porosome...
and release of secretory vesicles containing premade growth hormone.
Some Ca2+ influx is also a direct action of cAMP, which is distinct from the usual cAMP dependent pathway of activating protein kinase A.
Activation of GHRHRs by GHRH also conveys opening of Na+ channels by phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
, causing cell depolarization. The resultant change in the intracellular voltage opens a voltage-dependent calcium channel
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
, resulting in vesicle fusion
Vesicle fusion
Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis at the porosome...
and release of GH.
Relationship of GHRH and somatostatin
The actions of GHRH are opposed by somatostatinSomatostatin
Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.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.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
GHRH analog drug development
The GHRH analog tesamorelin (trade name Egrifta) is a drug for the treatment of lipodystrophyLipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
patients under highly active antiretroviral therapy, approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in November 2010. Chemically it is (3E)-hex-3-enoyl-GHRH. It may also reduce cognitive decline in older humans.
See also earlier work on Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys. CJC-1295
CJC-1295
CJC-1295 is a tetrasubstituted 30-amino acid peptide hormone, primarily functioning as a growth hormone releasing hormone analog. It was invented by ConjuChem, a Canadian biotechnology company....
, CJC-1293
CJC-1293
CJC-1293 or Modified GRF 1-29 , is a tetrasubstituted 29-amino acid peptide hormone, primarily functioning as a growth hormone releasing hormone analog with D-Ala, Gln, Ala, and Leu substitutions at positions 2, 8, 15, and 27 respectively...
and Sermorelin
Sermorelin
Sermorelin, sometimes called GRF 1-29, is a growth hormone releasing hormone analogue. It is a 29-amino acid polypeptide representing the 1-29 fragment from endogenous human growth hormone releasing hormone, and is thought to be the shortest fully functional fragment of GHRH. It is used as a test...
.