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GHSR
Identifiers
Aliases	GHSR, GHDP, growth hormone secretagogue receptor gene, growth hormone secretagogue receptor
External IDs	OMIM: 601898; MGI: 2441906; HomoloGene: 57161; GeneCards: GHSR; OMA:GHSR - orthologs
Gene location (Human) Chr. Chromosome 3 (human) Band 3q26.31 Start 172,443,291 bp End 172,448,456 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3|3 A3 Start 27,425,500 bp End 27,432,159 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Pituitary Gland islet of Langerhans anterior pituitary buccal mucosa cell granulocyte cecum gonad appendix Hypothalamus blood Top expressed in median eminence arcuate nucleus facial motor nucleus dentate gyrus of hippocampal formation granule cell mammillary body ventral tegmental area primary visual cortex neural tube Medulla Oblongata spinal cord More reference expression data BioGPS More reference expression data
Gene ontology Molecular function hormone binding signal transducer activity peptide hormone binding growth hormone-releasing hormone receptor activity growth hormone secretagogue receptor activity G protein-coupled receptor activity Cellular component integral component of membrane membrane cell surface neuron projection membrane raft plasma membrane Schaffer collateral - CA1 synapse postsynapse glutamatergic synapse integral component of synaptic membrane Biological process negative regulation of interleukin-1 beta production negative regulation of insulin secretion regulation of synapse assembly regulation of hindgut contraction decidualization positive regulation of insulin-like growth factor receptor signaling pathway positive regulation of fatty acid metabolic process hormone-mediated signaling pathway positive regulation of multicellular organism growth cellular response to insulin stimulus response to food response to hormone actin polymerization or depolymerization negative regulation of inflammatory response signal transduction positive regulation of appetite growth hormone secretion adult feeding behavior response to growth hormone positive regulation of eating behavior spermatogenesis female pregnancy learning or memory negative regulation of norepinephrine secretion negative regulation of appetite response to follicle-stimulating hormone response to estradiol ghrelin secretion regulation of transmission of nerve impulse regulation of growth hormone secretion cellular response to lipopolysaccharide response to dexamethasone negative regulation of locomotion involved in locomotory behavior cellular response to thyroid hormone stimulus positive regulation of sprouting angiogenesis response to monosodium glutamate regulation of gastric motility positive regulation of vascular endothelial cell proliferation cellular response to insulin-like growth factor stimulus negative regulation of macrophage apoptotic process positive regulation of growth regulation of feeding behavior positive regulation of small intestinal transit positive regulation of small intestine smooth muscle contraction G protein-coupled receptor signaling pathway regulation of neurotransmitter receptor localization to postsynaptic specialization membrane postsynaptic modulation of chemical synaptic transmission regulation of postsynapse organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2693 208188 Ensembl ENSG00000121853 ENSMUSG00000051136 UniProt Q92847 Q99P50 RefSeq (mRNA) NM_198407 NM_004122 NM_177330 RefSeq (protein) NP_004113 NP_940799 NP_796304 Location (UCSC) Chr 3: 172.44 – 172.45 Mb Chr 3: 27.43 – 27.43 Mb PubMed search
Wikidata
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Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a G protein-coupled receptor that binds growth hormone secretagogues (GHSs), such as ghrelin, the "hunger hormone". The role of GHS-R is thought to be in regulating energy homeostasis and body weight. In the brain, they are most highly expressed in the hypothalamus, specifically the ventromedial nucleus and arcuate nucleus. GSH-Rs are also expressed in other areas of the brain, including the ventral tegmental area, hippocampus, and substantia nigra. Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart.

Structure

Two identified transcript variants are expressed in several tissues and are evolutionarily conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for ghrelin; however, it may function to attenuate activity of isoform 1a.

GHS-R1a is a member of the G-protein-coupled receptor (GPCR) family. Previous studies have shown that GPCRs can form heterodimers, or functional receptor pairs with other types of G-protein coupled receptors (GPCRs). Various studies suggest that GHS-R1a specifically forms dimers with the following hormone and neurotransmitter receptors: somatostatin receptor 5, dopamine receptor type 2 (DRD2), melanocortin-3 receptor (MC3R), and serotonin receptor type 2C (5-HT_2c receptor). See "Function" section below for details on the purported functions of these heterodimers.

Function

Growth hormone release

The binding of ghrelin to GHS-R1a in pituitary cells stimulates the secretion, but not the synthesis, of growth hormone (GH) by the pituitary gland.

Constitutive activity

One important feature of GHS-R1a is that there is still some activity in the receptor even when it is not actively being stimulated. This is called constitutive activity, and it means that the receptor is always "on," unless acted on by an inverse agonist. This constitutive activity seems to provide a tonic signal required for the development of normal height, probably through an effect on the GH axis. In fact, some GHS-R1a genetic variations, caused by single nucleotide polymorphisms (SNPs), have been found to be associated with hereditary obesity and others with hereditary short stature. It was also found that, when GHS-R1A constitutive activity was diminished, there were decreased levels of hunger-inducing hormone neuropeptide Y (NPY) as well as in food intake and body weight.

Intracellular signaling mechanisms

When the growth hormone secretagogue receptor is activated, a variety of different intracellular signaling cascades can result, depending on the cell type in which the receptor is expressed. These intracellular signaling cascades include mitogen-activated protein kinase (MAPK)), protein kinase A (PKA), protein kinase B (PKB), also known as AKT), and AMP Activated Protein Kinase (AMPK) cascades.

Behavioral reinforcement of food intake

It is well-characterized that activating the growth hormone secretagogue receptor with ghrelin induces an orexigenic state, or general feeling of hunger. However, ghrelin may also play a role in behavioral reinforcement. Studies in animal models, found that food intake increased when ghrelin was specifically administered to just the ventral tegmental area (VTA), a brain area that uses dopamine signaling to reinforce behavior. In fact, the more ghrelin administered, the more food the rodent consumed. This is called a dose-dependent effect. Building on this, it was found that there are growth hormone secretagogue receptors in the VTA and that ghrelin acts on the VTA through these receptors. Current studies, furthermore, suggest that the VTA may contain dimers of GHS-R1a and dopamine receptor type 2 (DRD2). If these two receptors do indeed form dimers, this would somehow link ghrelin signaling to dopaminergic signaling.

Enhancement of learning and memory

The growth hormone secretagogue receptor may also be linked to learning and memory. First of all, the receptor is found in the hippocampus, the brain region responsible for long-term memory. Second, it was found that specifically activating the receptor in just the hippocampus increased both long-term potentiation (LTP) and dendritic spine density, two cellular phenomena thought to be involved in learning. Third, short-term calorie restriction, defined as a 30% reduction in caloric intake for two weeks, which naturally increases ghrelin levels and thus activates the receptor, was found to increase both performance on spatial learning tasks as well as neurogenesis in the adult hippocampus.

Selective ligands

A range of selective ligands for the GHS-R receptor are now available and are being developed for several clinical applications. GHS-R agonists have appetite-stimulating and growth hormone-releasing effects, and are likely to be useful for the treatment of muscle wasting and frailty associated with old-age and degenerative diseases. On the other hand, GHS-R antagonists have anorectic effects and are likely to be useful for the treatment of obesity.

Agonists

• Adenosine (increases hunger-related signaling, but does not promote GH secretion)
• Alexamorelin
• Anamorelin
• Capromorelin
• CP-464709
• Cortistatin-14
• Examorelin (hexarelin)
• Ghrelin (lenomorelin)
• GHRP-1
• GHRP-3
• GHRP-4
• GHRP-5
• GHRP-6
• Ibutamoren (MK-677)
• Ipamorelin
• L-692,585
• LY-426410
• LY-444711
• Macimorelin
• Pralmorelin (GHRP-2)
• Relamorelin
• SM-130,686
• Tabimorelin
• Ulimorelin

Antagonists

• A-778,193
• PF-5190457

References

1. ^ GRCh38: Ensembl release 89: ENSG00000121853 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000051136 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, et al. (December 2005). "International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function". Pharmacological Reviews. 57 (4): 541–546. doi:10.1124/pr.57.4.1. PMID 16382107. S2CID 11254096.
6. ^ Pradhan G, Samson SL, Sun Y (November 2013). "Ghrelin: much more than a hunger hormone". Current Opinion in Clinical Nutrition and Metabolic Care. 16 (6): 619–624. doi:10.1097/mco.0b013e328365b9be. PMC 4049314. PMID 24100676.
7. Pazos Y, Casanueva FF, Camiña JP (2008). "Basic aspects of ghrelin action". Ghrelin. Vitamins & Hormones. Vol. 77. pp. 89–119. doi:10.1016/S0083-6729(06)77005-4. ISBN 9780123736857. PMID 17983854.
8. ^ Andrews ZB (January 2011). "The extra-hypothalamic actions of ghrelin on neuronal function". Trends in Neurosciences. 34 (1): 31–40. doi:10.1016/j.tins.2010.10.001. PMID 21035199. S2CID 42200775.
9. ^ Yin Y, Li Y, Zhang W (March 2014). "The growth hormone secretagogue receptor: its intracellular signaling and regulation". International Journal of Molecular Sciences. 15 (3): 4837–4855. doi:10.3390/ijms15034837. PMC 3975427. PMID 24651458.
10. "Entrez Gene: GHS-R growth hormone secretagogue receptor".
11. ^ Schellekens H, Dinan TG, Cryan JF (August 2013). "Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward". Frontiers in Neuroscience. 7: 148. doi:10.3389/fnins.2013.00148. PMC 3757321. PMID 24009547.
12. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. (November 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology. 141 (11): 4325–4328. doi:10.1210/endo.141.11.7873. PMID 11089570.
13. Khatib N, Gaidhane S, Gaidhane AM, Khatib M, Simkhada P, Gode D, Zahiruddin QS (August 2014). "Ghrelin: ghrelin as a regulatory Peptide in growth hormone secretion". Journal of Clinical and Diagnostic Research. 8 (8): MC13–MC17. doi:10.7860/JCDR/2014/9863.4767. PMC 4190751. PMID 25302229.
14. Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, et al. (March 2006). "Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature". The Journal of Clinical Investigation. 116 (3): 760–768. doi:10.1172/jci25303. PMC 1386106. PMID 16511605.
15. Wang W, Tao YX (2016). "Ghrelin Receptor Mutations and Human Obesity". Genetics of Monogenic and Syndromic Obesity. Vol. 140. pp. 131–50. doi:10.1016/bs.pmbts.2016.02.001. ISBN 9780128046159. PMID 27288828. {{cite book}}: |journal= ignored (help)
16. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW (November 2003). "High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist". Molecular Endocrinology. 17 (11): 2201–2210. doi:10.1210/me.2003-0069. PMID 12907757.
17. Petersen PS, Woldbye DP, Madsen AN, Egerod KL, Jin C, Lang M, et al. (November 2009). "In vivo characterization of high Basal signaling from the ghrelin receptor". Endocrinology. 150 (11): 4920–4930. doi:10.1210/en.2008-1638. PMID 19819980.
18. ^ Lutter M, Elmquist J (August 2009). "Depression and metabolism: linking changes in leptin and ghrelin to mood". F1000 Biology Reports. 1 (63): 63. doi:10.3410/b1-63. PMC 2948264. PMID 20948621.
19. Kordon C, Robinson I, Hanoune J, Dantzer R (6 December 2012). Brain Somatic Cross-Talk and the Central Control of Metabolism. Springer Science & Business Media. pp. 42–. ISBN 978-3-642-18999-9.
20. Bhattacharya SK, Andrews K, Beveridge R, Cameron KO, Chen C, Dunn M, et al. (May 2014). "Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate". ACS Medicinal Chemistry Letters. 5 (5): 474–479. doi:10.1021/ml400473x. PMC 4027753. PMID 24900864.

Further reading

• Portelli J, Thielemans L, Ver Donck L, Loyens E, Coppens J, Aourz N, et al. (July 2012). "Inactivation of the constitutively active ghrelin receptor attenuates limbic seizure activity in rodents". Neurotherapeutics. 9 (3): 658–672. doi:10.1007/s13311-012-0125-x. PMC 3441926. PMID 22669710.

External links

• "Ghrelin Receptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-07-11. Retrieved 2007-10-25.
• growth+hormone+secretagogue+receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Ghrelin Archived 2008-05-12 at the Wayback Machine at Colorado State University

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Genes on human chromosome 3
• G protein-coupled receptors