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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/27 16:51:00」(JST)

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Growth hormone–releasing hormone (GHRH), also known as growth hormone–releasing factor (GRF, GHRF), somatoliberin, and somatocrinin in its endogenous forms and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44^[1]-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.^[1]

Origin

GHRH is released from neurosecretory nerve terminals of these arcuate neurons, and is carried by the hypothalamo-hypophyseal portal system 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.^[2] Growth hormone is required for normal postnatal growth, bone growth, regulatory effects on protein, carbohydrate, and lipid metabolism.^[1]

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 receptors, and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is approximately 44 kD.^[1]

Signal transduction

GHRH binding to GHRHR results in increased GH production mainly by the cAMP-dependent pathway,^[3] but also by the phospholipase C pathway (IP₃/DAG pathway),^[1] and other minor pathways.^[1]

The cAMP-dependent pathway 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 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.^[1]

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.^[1]

Some Ca²⁺ influx is also a direct action of cAMP, which is distinct from the usual cAMP-dependent pathway of activating protein kinase A.^[1]

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.^[1]

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.

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.^[1]

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

Analogs

Growth-hormone-releasing hormone is the lead compound for a number of structural and functional analogs, such as Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys,^[4] CJC-1293,^[5] and CJC-1295.^[6]

Many GHRH analogs remain primarily research chemicals, although some have specific applications. Sermorelin, a functional peptide fragment of GHRH, has been used in the diagnosis of deficiencies in growth hormone secretion.^[7] Tesamorelin,^[8] under the trade name Egrifta, received U.S. Food and Drug Administration approval in 2010 for the treatment of lipodystrophy in HIV patients under highly active antiretroviral therapy,^[9] and, in 2011, was investigated for effects on certain cognitive tests in the elderly.^[10] As a category, the use of GHRH analogs by professional athletes may be prohibited by restrictions on doping in sport because they act as growth hormone secretagogues.^[11]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009
^ Obál F, Krueger J (2001). "The somatotropic axis and sleep.". Rev Neurol (Paris) 157 (11 Pt 2): S12–5. PMID 11924022.
^ Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
^ Tang SS, Zhang JH, Du MH, Wu J, Liu JJ (2004). "Construction and activity of a novel GHRH analog, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys.". Acta Pharmacol. Sin. 25 (11): 1464–70. PMID 15525469.
^ Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP (2005). "Human Growth Hormone-Releasing Factor (hGRF)1–29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog". Endocrinology 146 (7): 3052–8. doi:10.1210/en.2004-1286. PMID 15817669.
^ Teichman, SL; et al. (2006). "Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults". J Clin Endocrinol Metab. 91 (3): 799–805. doi:10.1210/jc.2005-1536.
^ Prakash A, Goa KL (August 1999). "Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency". BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy 12 (2): 139–57. doi:10.2165/00063030-199912020-00007. PMID 18031173.
^ Mauss, Stefan; Schmutz, GüNther (2001). "Das HIV-assoziierte Lipodystrophiesyndrom". Medizinische Klinik 96 (7): 391–401. doi:10.1007/PL00002220. PMID 11494914.
^ "FDA approves Egrifta to treat Lipodystrophy in HIV patients". U.S. Food and Drug Administration. 2010-11-10. Retrieved 2013-09-13.
^ Gever, John (2011-07-11). "ICAD: Tesamorelin Boosts Cognition in Elderly". MedPage Today. Retrieved 2013-09-13.
^ Koh, Benjamin and Hardie, Martin (2013-02-11). "We need an advocate against ASADA’s power in doping control". The Conversation. Retrieved 2013-09-13.

English Journal

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs.

Moradi SV1, Varamini P, Toth I.
The AAPS journal.AAPS J.2015 Sep;17(5):1135-43. doi: 10.1208/s12248-015-9769-x. Epub 2015 May 9.
The enzymatic stability, antitumor activity, and gonadotropin stimulatory effects of glycosylated luteinizing hormone-releasing hormone (LHRH) analogs were investigated in this study. Conjugation of carbohydrate units, including lactose (Lac), glucose (GS), and galactose (Gal) to LHRH peptide protec
PMID 25956382

Structural analysis of Clostridium botulinum neurotoxin type D as a platform for the development of targeted secretion inhibitors.

Masuyer G1,2, Davies JR1, Moore K3, Chaddock JA3, Ravi Acharya K1.
Scientific reports.Sci Rep.2015 Sep 1;5:13397. doi: 10.1038/srep13397.
The botulinum neurotoxin type D is one of seven highly potent toxins produced by Clostridium botulinum which inhibit neurotransmission at cholinergic nerve terminals. A functional fragment derived from the toxin, LHn, consisting of the catalytic and translocation domains, has been heralded as a plat
PMID 26324071

Assessment of dose-effect and therapeutic time window in preclinical studies of rhEGF and GHRP-6 coadministration for stroke therapy.

Subirós N, Pérez-Saad HM, Berlanga JA, Aldana L, García-Illera G, Gibson CL, García-Del-Barco D.
Neurological research.Neurol Res.2015 Aug 27:1743132815Y0000000089. [Epub ahead of print]
BACKGROUND: Stroke continues to be a leading cause of mortality and morbidity worldwide, and novel therapeutic options for ischaemic stroke are urgently needed. In this context, drug combination therapies seem to be a viable approach, which has not been fully explored in preclinical studies.OBJECTIV
PMID 26311576

Related Pictures

★リンクテーブル★

リンク元	「成長ホルモン放出ホルモン」「ソマトリベリン」

「成長ホルモン放出ホルモン」

Growth hormone releasing hormone
Identifiers
Symbol	GHRH
Alt. symbols	GRF, GHRF
CAS number	9034-39-3
Entrez	2691
HUGO	4265
OMIM	139190
RefSeq	NM_021081
UniProt	P01286
Other data
Locus	Chr. 20 p12 or q11.2-q12

　　[★]

英: growth hormone-releasing hormone,growth hormone releasing hormone ,GHRH, GRH
同: ソマトトロピン放出ホルモン somatotropin-releasing hormone SRH、ソマトリベリン somatoliberin、成長ホルモン放出因子 growth hormone-releasing factor GRF
関: 成長ホルモン、視床下部ホルモン

「ソマトリベリン」

　　[★]

英: somatoliberin
関: 成長ホルモン放出ホルモン

[GeneGlobe-1] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k GeneGlobe -> GHRH Signaling Retrieved on May 31, 2009

[2] Obál F, Krueger J (2001). "The somatotropic axis and sleep.". Rev Neurol (Paris) 157 (11 Pt 2): S12–5. PMID 11924022.

[boron-3] Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.

[4] Tang SS, Zhang JH, Du MH, Wu J, Liu JJ (2004). "Construction and activity of a novel GHRH analog, Pro-Pro-hGHRH(1-44)-Gly-Gly-Cys.". Acta Pharmacol. Sin. 25 (11): 1464–70. PMID 15525469.

[Jette-5] Jetté L, Léger R, Thibaudeau K, Benquet C, Robitaille M, Pellerin I, Paradis V, van Wyk P, Pham K, Bridon DP (2005). "Human Growth Hormone-Releasing Factor (hGRF)1–29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog". Endocrinology 146 (7): 3052–8. doi:10.1210/en.2004-1286. PMID 15817669.

[6] Teichman, SL; et al. (2006). "Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults". J Clin Endocrinol Metab. 91 (3): 799–805. doi:10.1210/jc.2005-1536.

[pmid18031173-7] Prakash A, Goa KL (August 1999). "Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency". BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy 12 (2): 139–57. doi:10.2165/00063030-199912020-00007. PMID 18031173.

[8] Mauss, Stefan; Schmutz, GüNther (2001). "Das HIV-assoziierte Lipodystrophiesyndrom". Medizinische Klinik 96 (7): 391–401. doi:10.1007/PL00002220. PMID 11494914.

[9] "FDA approves Egrifta to treat Lipodystrophy in HIV patients". U.S. Food and Drug Administration. 2010-11-10. Retrieved 2013-09-13.

[10] Gever, John (2011-07-11). "ICAD: Tesamorelin Boosts Cognition in Elderly". MedPage Today. Retrieved 2013-09-13.

[11] Koh, Benjamin and Hardie, Martin (2013-02-11). "We need an advocate against ASADA’s power in doping control". The Conversation. Retrieved 2013-09-13.

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somatoliberin