Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GHSR: Growth Hormone Secretagogue Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101611

Synonyms

Historical Background

Growth hormone secretagogue receptor (GHSR) was first cloned from human hypothalamus and pituitary, with the function of binding growth hormone secretagogue (Howard et al. 1996). Both peptidyl and nonpeptidyl growth hormone secretagogues could activate the GHSR on membrane of somatotroph cells from anterior-pituitary (McKee et al. 1997). Three years later, its endogenous ligand was found in rat stomach extract by Kojima et al. This endogenous ligand for GHSR was named as ghrelin because ghr is the Proto-Indo-European root for grow (Kojima et al. 1999).

GHSR plays important roles in many canonical physiological functions when activated by its endogenous ligand ghrelin. Ghrelin is a 28 amino acid peptide released into blood in response to hormonal or neural signals. Activation of GHSR requires a unique octanoylation of the third amino acid serine of ghrelin. The physiological functions of GHSR include (Yin et al. 2014): (1) stimulation of the release of several hormones such as growth hormone, adrenocorticotropic hormone, and prolactin; (2) regulation of feeding behavior, as well as lipid, carbohydrate, and energy metabolism; (3) modulation of gastrointestinal motility and pancreas hormone secretion; (4) enhancement of cell proliferation and survival; (5) attenuation of inflammatory response; and (6) protection of nervous and cardiovascular system.

Structure and Ligand Activation Properties

GHSR is a G protein coupled receptor (GPCR) that contains the classic seven transmembrane (TM I-TM VII) domains like other members of GPCR family. GHSR gene is located in the human third chromosome 3q26.2. It contains two exons and one intron. Transmembrane I-V in amino terminus and transmembrane VI-VII in carboxyl terminus are encoded by two exons, respectively. Due to the stop codon location in the intron, there may occur alternative splicing. As a consequence, this gene segment could generate two transcription products: GHSR1a with full length (366 amino acids) and GHSR1b (289 amino acids) with only first five transmembrane domains and a tail from intron (McKee et al. 1997; Petersenn et al. 2001). GHSR1a is identified as the functional form and has been extensively studied. We therefore refer the GHSR1a as GHSR in rest of this chapter.

Similar to other transmembrane proteins, GHSR starts from the extracellular amino terminus, spans seven times across the cytoplasm membrane, then ends intracellularly with the carboxyl terminus. These seven transmembrane α-helix hydrophobic domains, which are connected by three intra- and extracellular domains, form a round calyx-like structure with the Pro residues in the center of the TM helices. TM III occupies the central position, while TM V is the most peripheral (Pedretti et al. 2006). TM II and TM III are the ligand activation domains. Three conserved residues, Glu140-Arg141-Tyr142, located at the intracellular end of TM III, are critical for the isomerization between the active and inactive conformation of GHSR. Two conserved cysteine residues (Cys116 and Cys198) on extracellular loops 1 and 2 form a disulfide bond (Schwartz et al. 2006; Petersenn 2002). These key amino acid residues are evolutionarily conserved for 400 million years and are essential for binding and activation of GHSR by different ligands.

Intracellular Signaling

Upon binding with its ligands, GHSR undergoes a profound change in the conformation. This conformational alteration facilitates its interaction with G-proteins, leading to subsequent initiation and activation of various signaling responses via a series of intracellular molecules.

[Ca2+]i Signaling

Activation of GHSR in pituitary cells triggers a rise in the intracellular calcium concentration ([Ca2+]i). Two mechanisms underlies the increment of [Ca2+]i: the phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP3) signaling pathway and protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) signaling pathway. Activation of GHSR releases Gαq/11 subunit, leading to the production of PLC. PLC then catalyzes phosphatidylinositol into IP3 and diacylglycerol (DAG). Upon binding with its receptors on the endoplasmic reticulum, IP3 opens the Ca2+ channels and triggers the release of Ca2+ from these Ca2+ storage pools. DAG activates protein kinase C (PKC) to inhibit the K+ channel, leading to the facilitation of Ca2+ influx through voltage gated calcium channels (Chen et al. 1990). Alternatively, GHSR may interact with Gαs protein to increase cAMP and to stimulate Ca2+ influx via N type calcium channels. The later mechanism has been observed in the hypothalamic neurons that contain neuropeptide Y (NPY) (Kohno et al. 2003).

AMPK/mTOR Signaling

AMP activated protein kinase (AMPK) is a critical intracellular signaling molecule in a wide range of cell types. Activation of GHSR has been reported to induce AMPK signaling in both the central neurons and peripheral cells such as cardiomyocytes and hepatocytes. The exact mechanism by which GHSR regulates AMPK signaling remains unknown, although tumor suppressor LKB1 may be an upstream mediator.

Central administration of ghrelin has been demonstrated to induce a marked upregulation of the mTOR signaling in the hypothalamic and dorsal vagal neurons, both of which express GHSR. These observations suggest that GHSR may activate mTOR signaling in neuronal cells. The molecular link between GHSR and mTOR signaling remains unknown. AMPK has long been considered as an upstream inhibitor of mTOR signaling and may therefore serve as a potential molecule bridging the GHSR and mTOR signaling. However, current observations do not fully support this concept. Both AMPK and mTOR activities are increased by ghrelin in the hypothalamic neurons. These observations contradict the classical view on the negative regulation of mTOR activity by AMPK. Other studies have shown that ghrelin increases phosphorylation of hypothalamic AMPK, while decreases the phosphorylation of mTOR (Stevanovic et al. 2012).

PI3K/AKT Signaling

Activation of GHSR by ghrelin increases insulin receptor substrate (IRS-1)-associated PI3K activity while inhibits Akt phosphorylation in hepatoma cells. Alteration of PI3K/AKT signaling increases gluconeogenesis by stimulating the mRNA expression of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme of gluconeogenesis that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate (Murata et al. 2002). Ghrelin also stimulates the GHSR-dependent IRS-1-associated PI3K/Akt signaling in 3T3-L1 preadipocytes. Inhibition of PI3K activity completely attenuates the effects of ghrelin on the proliferation and apoptosis of these cells. In addition, activation of GHSR by ghrelin increases both basal and insulin-stimulated glucose transport through the PI3K/Akt signaling in 3T3-L1 cells (Kim et al. 2004). Blockade of PI3K signaling by LY294002 attenuates the effect of ghrelin on glucose transport. In vascular endothelial cells, activation of GHSR has also been demonstrated to induce the PI3K/Akt signaling.

MAPK Signaling

A wealth of data indicates that GHSR activates MAP kinase (MAPK) signaling in a wide variety of cell types ranging from adrenal gland cells, myocytes, adipocytes to osteoblasts. Multiple signaling pathways may be involved in GHSR-dependent activation of MAPK signaling. In preadipocytes, pretreatment of cells with a Gαi/o inhibitor (pertussis toxin), PKC inhibitors (staurosporine and GF109203X), or a PI3K inhibitor (wortmannin) significantly attenuates GHSR-dependent ERK1/2 phosphorylation. In hepatoma cells expressing GHSR, ghrelin increases the MAPK signaling pathway characterized by Tyr phosphorylation of insulin receptor substrate-1 (IRS-1) and binding of growth factor receptor-bound protein 2 (GRB2) to IRS-1, an upstream signaling molecule of MAPK (Murata et al. 2002).

Physiological Functions

Stimulation of Hormone Release

Activation of GHSR stimulates the release of pituitary hormones such as growth hormone (GH), adrenocorticotropic hormone (ACTH), cortisol, and prolactin (PRL). In pituitary cells, both nonendogenous and endogenous GHSR agonists stimulate the release of GH in a [Ca2+]i-dependent manner (Kohno et al. 2003).

Regulation of Feeding Behavior

The hypothalamic arcuate nucleus, a circumventricular organ with a permeable blood–brain barrier, expresses GHSR. Activation of GHSR following systemic or intracerebroventricular (ICV) administration of ghrelin increases appetite and food intake. This effect is independent of the GH release. Although both systemic and ICV administration of ghrelin increase plasma GH, ICV administration of ghrelin is more efficient in stimulating food intake. The orexigenic effect of ghrelin is dependent on its receptor GHSR in the hypothalamus. [D-Lys3]-GHRP-6, a GHSR antagonist, suppresses ghrelin-induced feeding (Nakazato et al. 2001). Administration of ghrelin activates the hypothalamic regions critical for the regulation of feeding behavior. Within the arcuate nucleus, GHSR is mainly expressed in almost all neurons expressing neuropeptide Y (NPY)/agouti-related peptide (AgRP). Only 8% of proopiomelanocortin (POMC) neurons and 20–25% of GHRH neurons express GHSR. Antibodies against NPY or AgRP and antagonists for NPY receptor abolish ghrelin-induced increment in food intake. In addition, activation of GHSR may reduce the POMC neuronal activity through increase in inhibitory gamma-aminobutyric acidergic inputs from NPY/AgRP neurons. Thus, ghrelin may stimulate the food intake by simultaneously activating orexigenic NPY/AgRP neurons and suppressing anorexigenic POMC neurons.

Modulation of Glucose and Lipid Metabolism

Numerous studies support a role for GHSR in glucose homeostasis. First, ghrelin-GHSR signaling affects insulin secretion from pancreatic β cells. There exists an inverse relationship between blood ghrelin and insulin levels, suggesting an inhibitory feedback between these two hormones. Depending on experimental conditions, ghrelin either stimulates or inhibits insulin secretion. The mechanisms involved in the inhibition of glucose-induced insulin secretion upon activation of GHSR include the increased expression of the insulinoma-associated protein 2β (IA-2β) and activation of the AMPK-uncoupling protein 2 (UCP2) pathway (Doi et al. 2006). Second, activation of GHSR alters the insulin responsiveness of peripheral tissues. In adipose tissue, activation of GHSR increases insulin-stimulated glucose uptake by increasing the phosphorylation of IRS-1 and AKT (Kim et al. 2004). In skeletal muscle, ghrelin suppresses insulin-stimulated membrane translocation of glucose transporter 4 (Xu et al. 2012). In liver, ghrelin stimulates glycogenolysis and neoglucogenesis and prevents insulin-induced suppression of glucose production (Murata et al. 2002). A better understanding on how ghrelin-GHSR signaling modulates insulin secretion as well as glucose uptake and production requires additional experiments to unravel its influence on glucose homeostasis.

Activation of GHSR signaling increases lipid deposition in adipose tissue and liver. This effect occurs through both the central and peripheral mechanisms. Activation of hypothalamic GHSR stimulates triglyceride uptake and lipogenesis, while inhibiting lipid oxidation in white adipocytes. In brown adipocytes, central ghrelin decreases the expression of uncoupling proteins (UCPs) by the mediation of the sympathetic nervous system (Theander-Carrillo et al. 2006). Peripheral ghrelin increases visceral fat mass as measured by dual energy X-ray absorptiometry. Both genetic deletion and pharmacological blockade of GHSR abolishes the effect of ghrelin on adiposity, suggesting a GHSR-dependent mechanism (Tschop et al. 2000). Ghrelin-GHSR signaling also increases the lipid accumulation in liver (Li et al. 2014). Intervention of GHSR may attenuate the development of hepatic steatosis in both genetic and diet-induced obese models.

Gastrointestinal Functions

Activation of GHSR increases gastric acid and pancreatic secretion by a mechanism involving the vagus nerve and histamine synthesis and release. Ghrelin-GHSR signaling also enhances the after-contraction of gastric smooth muscle cells, although it has no effect on the contractility of human and rodent colon muscle strips. This effect involves the cholinergic and tachykinergic neurotransmission. As a result, ghrelin functions as prokinetic hormone to increase gastric emptying and intestinal transit both in rodents and human. Thus, ghrelin has important therapeutic potentials for gastrointestinal motility disorders.

Mitogenic Effects

GHSR regulates the proliferation and differentiation through MAPK signaling in a wide variety of cell types ranging from adrenal gland cells, myocytes, adipocytes to osteoblasts. Activation of GHSR stimulates the proliferation of human and rat adrenal zona glomerulosa cells through this mechanism. In preadipocytes, ghrelin-GHSR signaling demonstrates a mitogenic and antiapoptotic activity through the MAPK-dependent mechanism. Inhibition of MAPK signaling by PD98059, an ERK inhibitor, attenuates the mitogenic and antiapoptotic activities of ghrelin in these cells (Kim et al. 2004). In human embryonic stem cells (hESCs), ghrelin induces cardiomyocyte differentiation.

Effects on Immunity

Ghrelin-GHSR signaling exerts anti-inflammatory actions by inhibiting the production of proinflammatory cytokines in the inflammation models such as inflammatory bowel disease, pancreatitis, sepsis, arthritis, and diabetic nephropathy. Ghrelin administration prior to the development of experimental pancreatitis improves pancreatic blood flow, reduces IL1β levels, and stimulates pancreatic cell proliferation. In sepsis, ghrelin decreases norepinephrine and TNFα levels which are known to cause hepatocellular dysfunction. In addition, activation of macrophages is inhibited by ghrelin. Ghrelin decreases IL6 levels and symptoms of arthritis in an animal model. Activation of GHSR attenuates the development of experimental diabetic nephropathy in mice.

Cytoprotection

The cytoprotective effects of ghrelin-GHSR signaling have been reported in the circulation and nervous systems. Activation of GHSR inhibits apoptosis of cardiomyocytes and endothelial cells. This effect is mediated through the activation of extracellular signal-regulated kinase 1/2 and Akt serine kinases. The neuroprotective potential of ghrelin-GHSR signaling has been demonstrated in animal models of neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as other neuronal injuries such as ischemia or traumatic brain injury, spinal cord injury, and amyotrophic lateral sclerosis (Stoyanova 2014).

Summary

GHS-R1a is a seven transmembrane GPCR widely expressed in both the central nervous system and peripheral tissues such as pancreas, adipose tissue, heart, and blood vessel. Activation of GHSR requires a unique octanoylation of the third amino acid serine of its endogenous ligand: ghrelin. A wide variety of physiological functions have been described for this receptor. The regulation of food intake and energy homeostasis by GHSR has been the focus of studies in both the academy and industry. Therapeutic interest concerning GHSR for control of body weight and glucose and lipid dysfunction has been delayed because of inconsistent finding, differential response in distinct tissues and lack of long-term efficacy. Therefore, further investigation focused on the mechanism underlying the tissue-specific response in GHSR-mediated intracellular signaling, and the development of potent and safe GHSR antagonists may provide alternative strategies for the treatment of obesity and its related metabolic diseases.

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81330010, 81390354) and American Diabetes Association grant #1-13-BS-225.

References

  1. Chen C, Zhang J, Vincent JD, Israel JM. Two types of voltage-dependent calcium current in rat somatotrophs are reduced by somatostatin. J Physiol. 1990;425:29–42.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Doi A, Shono T, Nishi M, Furuta H, Sasaki H, Nanjo K. IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion. Proc Natl Acad Sci USA. 2006;103(4):885–90.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–7.PubMedCrossRefGoogle Scholar
  4. Kim MS, Yoon CY, Jang PG, Park YJ, Shin CS, Park HS, et al. The mitogenic and antiapoptotic actions of ghrelin in 3 T3-L1 adipocytes. Mol Endocrinol. 2004;18(9):2291–301.PubMedCrossRefGoogle Scholar
  5. Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T. Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes. 2003;52(4):948–56.PubMedCrossRefGoogle Scholar
  6. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedCrossRefGoogle Scholar
  7. Li Z, Xu G, Qin Y, Zhang C, Tang H, Yin Y, et al. Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARgamma signaling pathway. Proc Natl Acad Sci USA. 2014;111(36):13163–8.PubMedCrossRefPubMedCentralGoogle Scholar
  8. McKee KK, Palyha OC, Feighner SD, Hreniuk DL, Tan CP, Phillips MS, et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol. 1997;11(4):415–23.PubMedCrossRefGoogle Scholar
  9. Murata M, Okimura Y, Iida K, Matsumoto M, Sowa H, Kaji H, et al. Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J Biol Chem. 2002;277(7):5667–74.PubMedCrossRefGoogle Scholar
  10. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194–8.PubMedCrossRefGoogle Scholar
  11. Pedretti A, Villa M, Pallavicini M, Valoti E, Vistoli G. Construction of human ghrelin receptor (hGHS-R1a) model using a fragmental prediction approach and validation through docking analysis. J Med Chem. 2006;49(11):3077–85.PubMedCrossRefGoogle Scholar
  12. Petersenn S. Structure and regulation of the growth hormone secretagogue receptor. Minerva Endocrinol. 2002;27(4):243–56.PubMedPubMedCentralGoogle Scholar
  13. Petersenn S, Rasch AC, Penshorn M, Beil FU, Schulte HM. Genomic structure and transcriptional regulation of the human growth hormone secretagogue receptor. Endocrinology. 2001;142(6):2649–59.PubMedCrossRefGoogle Scholar
  14. Schwartz TW, Frimurer TM, Holst B, Rosenkilde MM, Elling CE. Molecular mechanism of 7TM receptor activation – a global toggle switch model. Annu Rev Pharmacol Toxicol. 2006;46:481–519.PubMedCrossRefGoogle Scholar
  15. Stevanovic D, Janjetovic K, Misirkic M, Vucicevic L, Sumarac-Dumanovic M, Micic D, et al. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signalling and food intake. Neuroendocrinology. 2012;96(1):24–31.PubMedCrossRefGoogle Scholar
  16. Stoyanova II. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders. Neurobiol Dis. 2014;72(Pt A):72–83.PubMedCrossRefGoogle Scholar
  17. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006;116(7):1983–93.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13.PubMedCrossRefGoogle Scholar
  19. Xu G, Wang Z, Li Y, Li Z, Tang H, Zhao J, et al. Ghrelin contributes to derangements of glucose metabolism induced by rapamycin in mice. Diabetologia. 2012;55(6):1813–23.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Yin Y, Li Y, Zhang W. The growth hormone secretagogue receptor: its intracellular signaling and regulation. Int J Mol Sci. 2014;15:4837–55.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Physiology and Pathophysiology, School of Basic Medical SciencesPeking University Health Science CenterBeijingChina
  2. 2.Department of SurgeryUniversity of Michigan Medical CenterAnn ArborUSA