Adenosine: A Partial Agonist of the Growth Hormone Secretagogue Receptor

Smith, Roy G.; Griffin, Patrick R.; Xu, Yuan; Smith, A.C.; Liu, Ken; Calacay, Jimmy; Feighner, Scott D.; Pong, C.-S.; Leong, Denis A.; Pomés, Anna; Cheng, Kang; Ploeg, Lex H.T. Van der; Howard, Andrew D.; Schaeffer, James M.; Leonard, Reid J.

doi:10.1006/bbrc.2000.3610

Cited by 64 publications

(56 citation statements)

References 34 publications

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“…Despite the extensive studies, there are basic questions remaining concerning ghrelin and its receptor. For example, adenosine is a partial agonist for the ghrelin receptor that binds to the receptor via a different site [87] and that mediates signals through different pathways [88]. In addition, while the acyl group on ghrelin is essential for it to stimulate GH production, both acyl and des-acyl ghrelin have anti-apoptotic effects on cardiac myocytes [89].…”

Section: Ghrelinmentioning

confidence: 99%

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network

Redelman¹,

Taub

et al. 2008

Cellular Immunology

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Neuroendocrine hormones such as growth hormone (GH) and prolactin (PRL) have been demonstrated to accelerate the recovery of the immune response after chemotherapy and bone marrow transplantation and to enhance the restoration of immunity in individuals infected with HIV and in normal individuals with compromised immune systems associated with aging. As the mechanism of action of these hormones has been elucidated, it has become clear that they are integral members of the immunological cytokine/chemokine network and share regulatory mechanisms with a wide variety of cytokines and chemokines. The members of this cytokine network induce and can be regulated by members of the suppressor of cytokine signaling (SOCS) family of intracellular proteins. In order to take advantage of the potential beneficial effects of hormones such as GH or PRL, it is essential to take into consideration the overall cytokine network and the regulatory effects of SOCS proteins.

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Section: Ghrelinmentioning

confidence: 99%

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network

Redelman¹,

Taub

et al. 2008

Cellular Immunology

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“…In addition, GHS-R1a appears to have other alternative ligands. This was revealed by studies carried out with adenosine (Smith et al 2000, Tullin et al 2000 and also with cortistatin (Deghenghi et al 2001). Indeed, administration of adenosine to cells not expressing the GHSR1a is devoid of action but when it is administered to cells expressing this receptor, adenosine triggers intracellular calcium rise, although it fails to stimulate growth hormone secretion (Tullin et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Adenosine does not bind to the growth hormone secretagogue receptor type-1a (GHS-R1a)

Carreira¹,

Camiña²,

Díaz‐Rodriguez³

et al. 2006

Journal of Endocrinology

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Ghrelin regulates GH secretion and energy homeostasis through the GH secretagogue receptor type-1a (GHS-R1a). This G-protein coupled receptor shows the peculiarity to transduce information provided not just by ghrelin as well as by adenosine through a supposed binding site different from the characterized ghrelin-binding pocket. Indeed, adenosine triggers intracellular calcium rise through a distinct signaling pathway to the one described for ghrelin, although it fails to stimulate GH secretion. Despite multiple active conformations of GHS-R1a, suggested as an explanation for a ligand-dependent activation of the downstream signaling, the concept of adenosine as agonist for GHS-R1a has been re-evaluated. The results revealed that calcium rise of both ghrelin and adenosine appears to be mediated by receptors that did not show the same sensitivity to protein kinase C (PKC) activity in GHS-R1a-transfected HEK 293 cells (HEK-GHS-R1a cells). The binding analyses showed the same number of adenosine-binding sites in both HEK 293 (B max Z2$01G0$15 fmol/cell) and HEK-GHS-R1a cells (B max Z1$90G0$11 fmol/cell). This binding was unaltered by different GHS-R1a antagonists. Western blot analysis showed a similar endogenous expression of endogenous adenosine receptor type-2b and -3 in both cell lines. The K d values for adenosine were 1$78 mM in HEK 293 cells and 6$30 mM in HEK-GHS-R1a cells, pointing to a modification of agonist affinity induced by overexpression of the GHSR1a. Additionally, adenosine failed to induce the GHS-R1a endocytosis, although it attenuates the ghrelin-induced GHSR1a endocytosis. In conclusion, adenosine is not an agonist of the GHS-R1a and its action is mediated by the endogenous adenosine receptor type-2b and -3, which is able to partially use the intracellular signaling machinery of HEK-GHS-R1a cells.

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“…Ghrelin and adenosine were identified as naturally occurring agonists for the orphan GHSR by fractionating and assaying animal tissue extracts in cell lines engineered to express the GHSR (11)(12)(13). Administration of ghrelin and adenosine to rats stimulates feeding, but only ghrelin stimulates GH release (12,14).…”

mentioning

confidence: 99%

Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

Sun

Wang

Zheng

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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661

530

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Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fastinginduced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.

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Adenosine: A Partial Agonist of the Growth Hormone Secretagogue Receptor

Cited by 64 publications

References 34 publications

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network

Neuroendocrine hormones such as growth hormone and prolactin are integral members of the immunological cytokine network

Adenosine does not bind to the growth hormone secretagogue receptor type-1a (GHS-R1a)

Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor

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