Growth hormone secretagogue receptor

Last updated
GHSR
Identifiers
Aliases GHSR , GHDP, growth hormone secretagogue receptor gene, growth hormone secretagogue receptor
External IDs OMIM: 601898 MGI: 2441906 HomoloGene: 57161 GeneCards: GHSR
Orthologs
SpeciesHumanMouse
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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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". [5] [6] The role of GHS-R is thought to be in regulating energy homeostasis and body weight. [7] 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. [8] Outside the central nervous system, too, GSH-Rs are also found in the liver, in skeletal muscle, and even in the heart. [9]

Contents

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. [10]

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, [6] dopamine receptor type 2 (DRD2), [11] melanocortin-3 receptor (MC3R), and serotonin receptor type 2C (5-HT2c receptor). [11] 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. [8] [12] [13]

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. [14] 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. [15] 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. [16] [17]

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) [9] ), protein kinase A (PKA), [9] protein kinase B (PKB), also known as AKT [9] ), and AMP Activated Protein Kinase (AMPK) cascades. [9]

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. [6] 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. [8] In fact, the more ghrelin administered, the more food the rodent consumed. [8] 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. [8] 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. [8]

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. [18] 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. [8] 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. [18]

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

Antagonists

Related Research Articles

<span class="mw-page-title-main">G protein-coupled receptor</span> Class of cell surface receptors coupled to G-protein-associated intracellular signaling

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 proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in form of six loops of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.

<span class="mw-page-title-main">Ghrelin</span> Peptide hormone involved in appetite regulation

Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.

<span class="mw-page-title-main">Motilin</span>

Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.

<span class="mw-page-title-main">Agouti-related peptide</span> Mammalian protein found in Homo sapiens

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus. AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.

Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by several other names in its endogenous forms and as somatorelin (INN) in its pharmaceutical form, is a releasing hormone of growth hormone (GH). It is a 44-amino acid peptide hormone produced in the arcuate nucleus of the hypothalamus.

<span class="mw-page-title-main">Follicle-stimulating hormone receptor</span> Protein-coding gene in the species Homo sapiens

The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary, testis, and uterus.

<span class="mw-page-title-main">Luteinizing hormone/choriogonadotropin receptor</span> Protein-coding gene in the species Homo sapiens

The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) is a transmembrane receptor found predominantly in the ovary and testis, but also many extragonadal organs such as the uterus and breasts. The receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.

<span class="mw-page-title-main">Constitutive androstane receptor</span> Protein-coding gene in humans

The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene. CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated. Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.

<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a receptor protein found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of G protein-coupled receptors. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">GHRP-6</span> Chemical compound

Growth hormone-releasing peptide 6 (GHRP-6), also known as growth hormone-releasing hexapeptide, is one of several synthetic met-enkephalin analogues that include unnatural D-amino acids, were developed for their growth hormone-releasing activity and are called growth hormone secretagogues. They lack opioid activity but are potent stimulators of growth hormone (GH) release. These secretagogues are distinct from growth hormone releasing hormone (GHRH) in that they share no sequence relation and derive their function through activation of a completely different receptor. This receptor was originally called the growth hormone secretagogue receptor (GHSR), but due to subsequent discoveries, the hormone ghrelin is now considered the receptor's natural endogenous ligand, and it has been renamed as the ghrelin receptor. Therefore, these GHSR agonists act as synthetic ghrelin mimetics.

G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

<span class="mw-page-title-main">GPR119</span> Protein-coding gene in humans

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

<span class="mw-page-title-main">GPR3</span> Protein

G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.

<span class="mw-page-title-main">Pancreatic polypeptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Pancreatic polypeptide receptor 1, also known as Neuropeptide Y receptor type 4, is a protein that in humans is encoded by the PPYR1 gene.

<span class="mw-page-title-main">Ibutamoren</span> Experimental drug

Ibutamoren (INN) is a potent, long-acting, orally-active, selective, and non-peptide agonist of the ghrelin receptor and a growth hormone secretagogue, mimicking the growth hormone (GH)-stimulating action of the endogenous hormone ghrelin. It has been shown to increase the secretion of several hormones including GH and insulin-like growth factor 1 (IGF-1) and produces sustained increases in the plasma levels of these hormones without affecting cortisol levels.

Cyril Y. Bowers, M.D., emeritus professor of medicine at Tulane University School of Medicine, attended medical school at the University of Oregon and did an internship at the University of Washington. He then studied biochemistry at Cornell University and attended the postgraduate school of medicine at the University of Pennsylvania. From 1961-2004 he was the director of the Section of Endocrinology & Metabolism in the department of medicine at Tulane University School of Medicine. Bowers has served on the editorial board of several endocrine journals, was a member of the National Institute of Diabetes and Digestive and Kidney Diseases Study Section for eight years and has written over 400 articles in peer-reviewed journals, including chapters in books and over 200 abstracts.

Growth hormone secretagogues or GH secretagogues (GHSs) are a class of drugs which act as secretagogues of growth hormone (GH). They include agonists of the ghrelin/growth hormone secretagogue receptor (GHSR), such as ghrelin (lenomorelin), pralmorelin (GHRP-2), GHRP-6, examorelin (hexarelin), ipamorelin, and ibutamoren (MK-677), and agonists of the growth hormone-releasing hormone receptor (GHRHR), such as growth hormone-releasing hormone, CJC-1295, sermorelin, and tesamorelin.

<span class="mw-page-title-main">Pralmorelin</span> Chemical compound

Pralmorelin (INN), also known as pralmorelin hydrochloride (JAN) and pralmorelin dihydrochloride (USAN), as well as, notably, growth hormone-releasing peptide 2 (GHRP-2), is a growth hormone secretagogue (GHS) used as a diagnostic agent that is marketed by Kaken Pharmaceutical in Japan in a single-dose formulation for the assessment of growth hormone deficiency (GHD).

<span class="mw-page-title-main">Ipamorelin</span> Peptide selective agonist of the ghrelin/growth hormone secretagogue receptor

Ipamorelin (INN) (developmental code name NNC 26-0161) is a peptide selective agonist of the ghrelin/growth hormone secretagogue receptor (GHS) and a growth hormone secretagogue. It is a pentapeptide with the amino acid sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 that was derived from GHRP-1.

<span class="mw-page-title-main">Examorelin</span> Chemical compound

Examorelin (INN) (developmental code names EP-23905, MF-6003), also known as hexarelin, is a potent, synthetic, peptidic, orally-active, centrally-penetrant, and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and a growth hormone secretagogue which was developed by Mediolanum Farmaceutici. It is a hexapeptide with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived from GHRP-6. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at the ghrelin receptor.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000121853 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 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. 1 2 3 4 5 6 7 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. 1 2 3 4 5 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. 1 2 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. 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. 1 2 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.

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