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

endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, es ...

forms and as somatorelin (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) in its

pharmaceutical form Dosage forms (also called unit doses) are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a cap ...

, is a

releasing hormone Releasing hormones and inhibiting hormones are hormones whose main purpose is to control the release of other hormones, either by stimulating or inhibiting their release. They are also called liberins () and statins () (respectively), or releasing ...

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

(GH). It is a 44-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

peptide hormone Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...

produced in the

arcuate nucleus The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...

of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

. 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.

Nomenclature

* Endogenous: ** somatocrinin ** somatoliberin ** growth hormone–releasing hormone (GHRH or GH-RH;

HGNC The HUGO Gene Nomenclature Committee (HGNC) is a committee of the Human Genome Organisation (HUGO) that sets the standards for human gene nomenclature. The HGNC approves a ''unique'' and ''meaningful'' name for every known human gene, based on a q ...

symbol is GHRH) ** growth hormone–releasing factor (GHRF or GRF) ** somatotropin-releasing hormone (SRH) ** somatotropin-releasing factor (SRF) * Pharmaceutical: ** somatorelin (

)

Origin

GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-

hypophyseal portal system The hypophyseal portal system is a system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary. Its main function is to quickly transport and exchange hormones between the hypo ...

to the

anterior pituitary gland A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

, where it stimulates

(GH) secretion by stimulating the

growth hormone-releasing hormone receptor The growth-hormone-releasing hormone receptor (GHRHR) is a G-protein-coupled receptor that binds growth hormone-releasing hormone. The GHRHR activates a Gs protein that causes a cascade of cAMP via adenylate cyclase. Function This gene, exp ...

. GHRH is released in a pulsatile manner, stimulating similar pulsatile release of GH. In addition, GHRH also promotes

slow-wave sleep Slow-wave sleep (SWS), often referred to as deep sleep, consists of stage three of non-rapid eye movement sleep. It usually lasts between 70 and 90 minutes and takes place during the first hours of the night. Initially, SWS consisted of both St ...

directly. Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.GeneGlobe -> GHRH Signaling
Retrieved on October 5, 2020

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 Glucagon/gastric inhibitory polypeptide/secretin/vasoactive intestinal peptide hormones are a family of evolutionarily related peptide hormones that regulate activity of G-protein-coupled receptors from the secretin receptor family. A number of ...

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s, and is located on

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...

in humans. 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 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. Discovery cAMP was discovered by Earl Sutherlan ...

, but also by the phospholipase C pathway (IP₃/DAG pathway), and other minor pathways. The

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 Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

and increased intracellular

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP). cAMP binds to and activates the regulatory subunits of

protein kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...

(PKA), allowing the free catalytic subunits to translocate to the nucleus and phosphorylate the transcription factor

cAMP response element-binding protein CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...

(CREB). Phosphorylated CREB, together with its coactivators, p300 and

CREB-binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...

(CBP) enhances the transcription of GH by binding to CREs cAMP-response elements in the

promoter region In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...

of the GH gene. It also increases transcription of the GHRHR gene, providing

positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...

. In the phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through the βγ-complex of heterotrimeric G-proteins. PLC activation produces both

diacylglycerol A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as sur ...

(DAG) and

inositol triphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...

(IP₃), the latter leading to release of intracellular Ca²⁺ from the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

, increasing cytosolic Ca²⁺ concentration, resulting in

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. Vesicles c ...

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+ channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...

s by

phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...

, causing cell depolarization. The resultant change in the intracellular voltage opens a

voltage-dependent calcium channel Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabi ...

, resulting in

and release of GH.

Relationship of GHRH and somatostatin

The actions of GHRH are opposed by

somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-couple ...

(growth-hormone-inhibiting hormone). Somatostatin is released from neurosecretory nerve terminals of periventricular somatostatin neurons, and is carried by the hypothalamo-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.

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 Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...

(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 A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, b ...

for a number of

structural A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such a ...

and functional analogs, such as Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys, CJC-1293, and

CJC-1295 CJC-1295, also known as DAC:GRF (short for drug affinity complex:growth hormone-releasing factor), is a synthetic analogue of growth hormone-releasing hormone (GHRH) (also known as ''growth hormone-releasing factor'' (''GRF'')) and a growth horm ...

. Many GHRH analogs remain primarily

research chemicals Research chemicals are chemical substances used by scientists for medical and scientific research purposes. One characteristic of a research chemical is that it is for laboratory research use only; a research chemical is not intended for human o ...

, although some have specific applications.

Sermorelin Sermorelin acetate (; brand names Geref, Gerel), also known as GHRH (1-29), is a peptide analogue of growth hormone-releasing hormone (GHRH) which is used as a diagnostic agent to assess growth hormone (GH) secretion for the purpose of diagno ...

, a functional

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

fragment of GHRH, has been used in the diagnosis of deficiencies in growth hormone secretion. Tesamorelin, under the trade name Egrifta, received U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

approval in 2010 for the treatment of

lipodystrophy Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. ...

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

patients under

highly active antiretroviral therapy The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple ...

, and, in 2011, was investigated for effects on certain cognitive tests in the elderly. As a category, the use of GHRH analogs by professional athletes may be prohibited by restrictions on

doping in sport In competitive sports, doping is the use of banned athletic performance-enhancing drugs by athletic competitors as a way of cheating in sports. The term ''doping'' is widely used by organizations that regulate sporting competitions. The use of ...

because they act as growth hormone

secretagogue A secretagogue is a substance that causes another substance to be secreted. The word comes from Greek ''agōgos'', meaning "a leader" or "bringer"; thus "something that brings secretions". The same root is seen in completely unrelated words such as ...

References

{{DEFAULTSORT:Growth hormone-releasing hormone Peptide hormones Hormones of the somatotropic axis Neuroendocrinology Human hormones Growth hormone secretagogues Growth hormone-releasing hormone receptor agonists