GHRH
Hormones

Author: stefano de donno
Date: 09/02/2014

Description

DEFINITION

Growth-hormone-releasing hormone (GHRH) is a releasing hormone for growth hormone.
It is a 44 amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus. Is the main regulator of pituaitary somatotrophs,GHRH binds to its G-protein coupled receptor (GHRH-R) to activate diverse signaling patways predominantly involving cAMP and Ca2+ and therey stimulates Gh Secretion.

GHRH is a member of a growing superfamily of brain-gut peptides, which also includes, among other, pituitary adenylate cyclase-activating polypeptide (PACAP), glucagon, secretin, and vasoactive intestinal polypeptide (VIP).

GHRH (growth hormone releasing hormone) is a protein-coding gene. Diseases associated with GHRH include gigantism, and carcinoid syndrome, and among its related super-pathways are Rac1 Pathway and Ras Pathway. GO annotations related to this gene include growth hormone-releasing hormone receptor binding and growth hormone-releasing hormone activity.

THE GENE

The protein encoded by this gene belongs to the glucagon family and is a preproprotein that is produced in the hypothalamus. The preproprotein is cleaved to form a 44 aa factor, also called somatocrinin, that acts to stimulate growth hormone release from the pituitary. Variant receptors for somatocrinin have been found in several types of tumors, and antagonists of these receptors can inhibit the growth of the tumors. Defects in this gene are a cause of dwarfism, while hypersecretion of the encoded protein is a cause of gigantism. [provided by RefSeq, Jul 2008]

DatabaseLink
CAS9034-39-3
HUGO4265
OMIM139190
Locuschr.20 p12 or q11.2-q12

The Ghrh gene is located on chromosome 20 and spans over 9 kilobases; the gene has five exons and four introns.The GHRH sequence has an arginine (Arg) residue at the terminal end which serves as a signal for proteolytic processing.

CHEMICAL STRUCTURE AND IMAGES

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

Protein Aminoacids Percentage (Width 700 px)

SYNTHESIS AND TURNOVER

The human pancreatic tumor samples that enabled isolation of GHRH also provided the first cDNA sequences, whose cloning and characterization revealed that GHRH mRNA codes for a pre-pro GHRH of 108 amino acids composed of a typical signal peptide, the 44-amino-acid Ghrh, and a 31 amino acid C-terminal peptide. A second isoform coding for a 107 amino-acid precursor lacking the ser-103 in the C-peptde was also found. Subsequently, the cDNA and/ or gene was isolated and characterized in rat, mouse, and other mammals, as well as, in birds, amphibians, and fish. In nonmammalian species, Ghrh is encoded together with PACAP by a common precursor gene.The primary stucture of GHRH is highly variable among species, especially at the C- terminus.In fact, rat GHRH, which is a 43 amino acids, shares 68 % homology with the human peptide, yet the N-terminal two-Thirds of the molecule, corresponding to the bioactive core of the peptide are more conserved.

GHRH protein expression

GHRH expression in normal human tissues (normalized intensities)

Degradation: Ghrh can be inactivated by peptidases.The remove the N- terminal peptide (Try-Ala) and cleave Ghrh at positions 2 and 3 to make in inactive as a fragment (3-44)-NH2.

CELLULAR FUNCTIONS

1 GHRH neurons are localized in the arcuate nucleus, the supraoptic nucleus (SON), and paraventricular nucleus (PVN) of the hypothalamus and pituitary stalk. SON and PVN neurons secrete GHRH into the pituitary portal system from the median eminence. Ghrh and somatostatin containing neurons are closely opposed in the hypothalamic arcuate and ventromedial nuclei.GHRH is present in the limbic system structures, cerebral cortex, and hindbrain region, as well as in the peripheral nervous system, gastrointestinal (GI) tract, pituitary, gonads, adrenal, thyroid,lung, and kidney.

2 In 1982, GHRH was isolated, sequenced ,and synthesized from 2 patients with GHRH-secreting pancreatic tumor. GHRH stimulates Gh synthesis and release and the proliferation and differentiation of pituaitary somatotrophs starting in the fetus. GHRH is secreted in a pulsatile manner about every 3 h and more frequently during sleep. The pulsatile release of GHRH is age dependent and there is also a sexually dimorphic pattern, particularly at puberty when ghrh function become less responsive to testosterone and the feedback of Gh on GHRh neurons also declines considerably with aging. In aging,GHRH receptor diminish. Ghrh also can regulate sleep, specifically it can increase the duration of slow wave sleep while at the same time inhibiting the secretion of ACTH and cortisol.

GHRH-RECEPTOR

The GHRH receptor is a seven-transmembrane G proteincoupled receptor that, in rat and human, is 423 amino acids in length. The GHRH receptor is a member of the B-III subfamily of G protein-coupled receptors, which includes the secretin/glucagon peptide receptors. Alternative splicing in G protein-coupled receptors is one of many emerging mechanisms by which this class of receptors diversifies its activities. The GHRH-RECEPTOR gene in localized to human chromosome 7p 14-15 and rat chromosome 4p24. The main form of GHRH-RECEPTOR in most mammals is a 423 amino-acid protein.

Protein Aminoacids Percentage (Width 700 px)

Signal transduction

GHRH binding to GHRHR results in increased GH production mainly by the cAMP dependent pathway, 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.

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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.

Clinical implication

Acromegaly is a syndrome caused by excessive circulation growth-hormone, most often as a result of a growth hormone secreting pituaitary tumor. Ghrh producing tumors are nevertheless an important, if relatively infrequent, cause of acromegaly and quantification of circulating Ghrh is an important element in the clinical evaluation of the syndrome. Pharmacologic treatment of acromegaly, notwith-standing surgery and radiation, is used in the attempt to reduce growth hormone hypersecretion. Administration of long-acting somatostatin analogues such as octreotide or a dopamine agonist, such as bromocriptine, for this purpose show varying degrees of success in reducing growth hormone concentrations.

Stefano De Donno
Giulia Pera

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