Structure−Function Studies on the New Growth Hormone-Releasing Peptide, Ghrelin:  Minimal Sequence of Ghrelin Necessary for Activation of Growth Hormone Secretagogue Receptor 1a

Bednarek, Maria A.; Feighner, Scott D.; Pong, Sheng-Shung; McKee, Karen K.; Hreniuk, Donna L.; Silva, M V; Warren, Vivien A.; Howard, Andrew D.; Ploeg, L H Van der; Heck, James V.

doi:10.1021/jm0001727

Cited by 518 publications

(475 citation statements)

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“…The same action was found to be exerted by des-Gln 14 -ghrelin, another natural acylated form of ghrelin derived from an alternative splicing of the ghrelin gene also capable of binding the GHS type 1a receptor (Hosoda et al, 2000a). However, we have now found unexpectedly that non-acylated ghrelin was able to exert the same action at even greater extent than the acylated forms of ghrelin, even though unacylated ghrelin is generally assumed to be devoid of biological activity (Kojima et al, 2001), as it cannot bind and activate the GHS type 1a receptor (Bednarek et al, 2001). Although GHS type 1a receptor expression at the myocardial level has been demonstrated (Nagaya and Kangawa, 2003), the existence of GHS receptor subtypes in the heart has been already shown .…”

Section: Discussionmentioning

confidence: 87%

“…Interestingly, the most significant influence on contractility of the papillary muscle was exerted by des-octanoyl ghrelin, an unacylated form devoid of any endocrine action (Kojima et al, 2001;Torsello et al, 2002) because this form, unlike octanoylated ghrelin and des-Gln 14 -ghrelin (Hosoda et al, 2000a), is unable to bind the classical GHS type 1a receptor (Bednarek et al, 2001). The binding studies performed here with either acylated and unacylated ghrelin demonstrated that there is a specific receptor recognized by all ghrelin forms and by hexarelin as well; these findings therefore indicate the existence of a cardiac non-GHS type 1a receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Both exist in either acylated and, more abundantly, non-acylated form (Hosoda et al, 2000b), but the latter have been shown inactive in term of endocrine activities (Kojima et al, 2001). They do not stimulate GH secretion in vivo (Torsello et al, 2002) because do not bind and activate the GHS type 1a receptor (Bednarek et al, 2001) neither displace radiolabelled ghrelin from its hypothalamo-pituitary binding sites Torsello et al, 2002). The gastric peptide ghrelin is endowed with a strong stimulatory effect on GH release, gastric acid secretion and gut motility in rats and humans (Kojima et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

169

116

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The mechanisms underlying the cardiac activities of synthetic growth hormone secretagogues (GHS) are still unclear. The natural ligand of the GHS receptors, i.e. ghrelin, classically binds the GHS receptor and exerts endocrine actions in acylated forms only; its cardiovascular actions still need to be investigated further. In order to clarify these aspects, we studied the effects of either the synthetic peptidyl GHS hexarelin (1 AM), or the natural ghrelin (50 nM) and the endogenous ghrelin derivatives des-Gln 14 -ghrelin (1 -100 nM) and des-octanoyl ghrelin (50 nM), on the tension developed by guinea pig papillary muscle and on L-type Ca 2 + current (I Ca ) of isolated ventricular cells. The binding of these molecules to ventricular cell membrane homogenates was also studied. We observed that all peptides reduced the tension developed at low frequencies (60 -120 beats/min) in a dose-dependent manner. No alteration in cardiac contractility was induced by desGln 14 -ghrelin or des-octanoylated ghrelin when the endocardial endothelium had been removed or after cyclooxygenase blockade. Pretreatment with tyramine (2 AM) had no effect on the inotropic response induced by des-Gln 14 -ghrelin. No significant effect on I Ca of isolated ventricular cells was observed in the presence of des-Gln 14 -ghrelin (100 nM). The order of potency on the tension of papillary muscle was: des-octanoyl ghrelin>ghrelin = des-Gln 14 -ghrelin>hexarelin. This gradient of potency was consistent with the binding experiments performed on ventricular membranes where either acylated or unacylated ghrelin forms, and hexarelin, recognized a common high-affinity binding site. In conclusion, ghrelin, des-Gln 14 -ghrelin and des-octanoyl ghrelin, show similar negative inotropic effect on papillary muscle; as des-octanoyl ghrelin is peculiarly devoid of any GH-releasing activity, the cardiotropic action of these molecules is independent of GH release. The binding studies and the experiments performed both on the isolated cells and on papillary muscle after endothelium removal or cyclooxygenase blockade indicate that the cardiotropic action of natural and synthetic ghrelin analogues reflects the interaction with a novel GHS receptor (peculiarly common for ghrelin and des-octanoyl ghrelin), leading to release of cyclooxygenase metabolites from endothelial cells, as indicated by direct measurement of prostacyclin metabolite 6-keto-PGF 1a .

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Bedendi

Alloatti

Marcantoni

et al. 2003

European Journal of Pharmacology

169

116

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“…Although it is known that C-terminal elongation of ghrelin hardly induces differences in potency [36], it is unknown whether this has an effect on desensitization. Using HEK293 cells stably transfected with the hGHSR, we also investigated different truncated forms of ghrelin.…”

Section: Ghsr Desensitization Is Essential For the Anticonvulsant Effmentioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

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“…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].…”

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confidence: 99%

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

Rocha‐Sousa

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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Structure−Function Studies on the New Growth Hormone-Releasing Peptide, Ghrelin: Minimal Sequence of Ghrelin Necessary for Activation of Growth Hormone Secretagogue Receptor 1a

Cited by 518 publications

References 18 publications

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

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