Agonist-Specific Coupling of Growth Hormone Secretagogue Receptor Type 1a to Different Intracellular Signaling Systems

Carreira, Marcos C.; Camiña, Jesús P.; Smith, Roy G.; Casanueva, Felipe F.

doi:10.1159/000076042

Cited by 48 publications

(35 citation statements)

References 29 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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“…Studies on sbGHSR-1a signal transduction reported herein show no evidence for the activation or inhibition of adenylate cyclase activity, providing direct evidence, at least in seabream, that GHSR-1a does not affect adenylate cyclase. During the preparation of this manuscript, Carreira et al [40] reported a similar finding that human GHSR-1a expressed in HEK293 cells did not trigger cAMP production when stimulated by ghrelin. In view of the fact that previously obtained results on the species differences in GHSR signaling have been conducted in primary cells from tissues, a revisit of the signaling mechanism by transfection of the receptor constructs in cultured cell lines is highly warranted.…”

Section: Discussionmentioning

confidence: 65%

Signal transduction mechanism of the seabream growth hormone secretagogue receptor

Chan¹,

Leung²,

Wise³

et al. 2004

FEBS Letters

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We have recently cloned the full-length cDNAs of the two growth hormone secretagogue receptor (GHSR) subtypes from a teleost species, the black seabream (Acanthopagrus schlegeli) [Mol. Cell. Endocrinol. 214 (2004) ] i ), whereas sbGHSR-1b appeared to play an inhibitory role on the signal transduction activity of sbGHSR-1a. In the present study, we have further investigated the signal transduction mechanism of sbGHSR-1a. The peptide GHS GHRP-6 and the non-peptide GHS L163,540 were able to trigger a receptor specific and phospholipase C (PLC)-dependent elevation of [Ca 2+ ] i in HEK293 cells stably expressing sbGHSR-1a. This GHS-induced calcium mobilization was also dependent on protein kinase C activated L-type calcium channel opening. It was found that sbGHSR-1a could function in an agonist-independent manner as it exhibited a high basal activity of inositol phosphate production in the absence of GHS, indicating that the fish receptor is constitutively active. In addition, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) were found to be activated upon stimulation of sbGHSR-1a by GHRP-6. This observation provides direct evidence in the coupling of sbGHSR-1a to ERK1/2 activation. Neither G s nor G i proteins are coupled to the receptor, as GHS did not induce cAMP production nor inhibit forskolin-stimulated cAMP accumulation in the sbGHSR-1a bearing cells. Furthermore, the ability of the GHSR antagonist D D -Lys(3)-GHRP-6 to inhibit basal PLC and basal ERK1/2 activity suggests that this compound is an inverse agonist. In summary, the sbGHSR-1a appears to couple through the G q=11 -mediated pathway to activate PLC, resulting in increased IP 3 production and Ca 2+ mobilization from both intracellular and extracellular stores. Moreover, sbGHSR-1a may trigger multiple signal transduction cascades to exert its physiological functions.

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“…The first one, the common binding site for ghrelin, is the transmembranar domain 3 [32], while the second was proposed to be an adenosine binding site [33]. This purine triggers a rise in intracellular calcium [34,35].…”

Section: Ghrelin Receptorsmentioning

confidence: 99%

“…This purine triggers a rise in intracellular calcium [34,35]. However, recent reports proposed that this could be an action of adenosine in the A 2B R purinergic receptor [33,34]. After its activation GHSR-1a promotes the activation of phospholipase C (PLC), phosphatidyl-inositol-4,5-biphosphate hydrolysis with the formation of diacylglyceride (DAG) and inositol triphosphate (IP 3 ).…”

Section: Ghrelin Receptorsmentioning

confidence: 99%

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

Rocha‐Sousa¹

2012

TOCVJ

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Ghrelin and obestatin are two different peptides originated from the same gene isolated in the stomach. Numerous actions have been described where these two peptides are implicated in metabolism, appetite regulation, glucose levels regulation, and a wide range of systemic effects. In this article, we summarize (1) the cellular receptors implicated in ghrelin and obestatin effects; (2) the role of ghrelin and obestatin in metabolism and appetite regulation; (3) their role in the glucose homeostasis regulation and its implication in diabetes patho-physiology; (5) the effects of ghrelin and obestatin in regulation of normal angiogenesis and (6) their possible role in the regulation of diabetes-induced pathologic angiogenesis.Keywords: Ghrelin, obestatin, diabetes pathophysiology, appetite regulation, peptides, diabetes vascular complications. GHRELINGhrelin is an acylated, 28-amino-acid peptide that promotes the release of GH in the hypothalamus. It is the natural ligand of the GHSR-1a receptor [1]. For it to act on the GHSR-1a ghrelin has an n-octanoic acid modification on serine 3 residue [2].The ghrelin gene is located in chromosome 3 (3p25-26) [1], contains four preproghrelin-coding exons, and encodes a precursor of 117aa (preproghrelin) with 82% of homology between species [3]. As a result of alternative splicing of this gene, a 27 aa acylated peptide was identified with the same activity potency as ghrelin (des-Gln14-ghrelin) [4]. Another form of ghrelin, des-acyl ghrelin, exists at significant levels in both stomach and blood. This variant lacks the octanoyl chain in serine 3 and represents more than 90% of the circulating peptide [2,4,5]. In plasma, acyl ghrelin levels are 10-20 fmol/ml while total ghrelin levels are 100-150 fmol/ml (including both acyl and non-acyl forms) [6,7]. Several minor forms of ghrelin were described with modifications on the peptide chain or on the acidic chain and are only present in low amounts [4,8]. Some of these are independently produced and regulated and their levels are not directly related to those of ghrelin [3]. Finally, in a posttranslational process, this gene can originate a 23 aa peptide named obestatin that has some different and even opposite actions than ghrelin [9].During adult life ghrelin is synthesized mainly in the gastric oxyntic mucosa in the X/A cells. Ghrelin is also produced in the X/A cells of the intestine and in some others tissues such as the pancreas, kidney, placenta, lymphatics, *Address correspondence to this author at the Department of Physiology, Faculty of Medicine, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Tel: +351 225513644; Fax: +351 225513646; E.mail: arsousa@med.up.pt # Both authors had the same contribution to the article gonads, adrenal, thyroid gland, heart, lung, pituitary, hypothalamus, eye [10], human B-and T-lymphocytes, neutrophils [1,[10][11][12], morula, blastocyts and embryos [13]. Ghelardoni observed that ghrelin gene expression and its protein were, in some tissues, dissociated [14].In fetal lif...

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Agonist-Specific Coupling of Growth Hormone Secretagogue Receptor Type 1a to Different Intracellular Signaling Systems

Cited by 48 publications

References 29 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

Signal transduction mechanism of the seabream growth hormone secretagogue receptor

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

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