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Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a.

ABSTRACT: Ghrelin synergizes with growth hormone-releasing hormone (GHRH) to potentiate growth hormone (GH) response through a mechanism not yet fully characterized. This study was conducted to analyze the role of GHRH as a potential ligand of the ghrelin receptor, GHS-R1a. The results show that hGHRH(1-29)NH(2) (GHRH) induces a dose-dependent calcium mobilization in HEK 293 cells stably transfected with GHS-R1a an effect not observed in wild-type HEK 293 cells. This calcium rise is also observed using the GHRH receptor agonists JI-34 and JI-36. Radioligand binding and cross-linking studies revealed that calcium response to GHRH is mediated by the ghrelin receptor GHS-R1a. GHRH activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover. The presence of GHRH increases the binding capacity of (125)I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity. In addition, confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that GHRH activates the GHS-R1a endocytosis. Furthermore, the selective GHRH-R antagonists, JV-1-42 and JMR-132, act also as antagonists of the ghrelin receptor GHS-R1a. Our findings suggest that GHRH interacts with ghrelin receptor GHS-R1a, and, in consequence, modifies the ghrelin-associated intracellular signaling pathway. This interaction may represent a form of regulation, which could play a putative role in the physiology of GH regulation and appetite control.

SUBMITTER: Casanueva FF

PROVIDER: S-EPMC2603429 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling.

Project description:G protein-coupled receptors (GPCRs), such as the ghrelin receptor (GHS-R1a), the melanocortin 3 receptor (MC(3)), and the serotonin 2C receptor (5-HT(2C)), are well known for their key role in the homeostatic control of food intake and energy balance. Ghrelin is the only known gut peptide exerting an orexigenic effect and has thus received much attention as an anti-obesity drug target. In addition, recent data have revealed a critical role for ghrelin in dopaminergic mesolimbic circuits involved in food reward signaling. This study investigates the downstream signaling consequences and ligand-mediated co-internalization following heterodimerization of the GHS-R1a receptor with the dopamine 1 receptor, as well as that of the GHS-R1a-MC(3) heterodimer. In addition, a novel heterodimer between the GHS-R1a receptor and the 5-HT(2C) receptor was identified. Interestingly, dimerization of the GHS-R1a receptor with the unedited 5-HT(2C)-INI receptor, but not with the partially edited 5-HT(2C)-VSV isoform, significantly reduced GHS-R1a agonist-mediated calcium influx, which was completely restored following pharmacological blockade of the 5-HT(2C) receptor. These results combined suggest a potential novel mechanism for fine-tuning GHS-R1a receptor-mediated activity via promiscuous dimerization of the GHS-R1a receptor with other G protein-coupled receptors involved in appetite regulation and food reward. These findings may uncover novel mechanisms of significant relevance for the future pharmacological targeting of the GHS-R1a receptor in the homeostatic regulation of energy balance and in hedonic appetite signaling, both of which play a significant role in the development of obesity.

| S-EPMC3537012 | biostudies-literature

Therapeutic effects of acylated ghrelin-specific receptor GHS-R1a antagonist in islet transplantation.

Project description:Islet transplantation is a type of cellular replacement therapy for severe diabetes that is limited by compromising effect on engrafted islets. Trials aiming to improve the function of transplanted islets have also been challenging. This study attempted to elucidate whether regulation of growth hormone secretagogue receptor-1a (GHS-R1a), one of the ghrelin receptors, improve the therapeutic effects of islet transplantation using [D-Lys3]-GHRP-6 (DLS), a specific GHS-R1a antagonist. The therapeutic effects of DLS were assessed in terms of the expression/production of endocrine genes/proteins, insulin-releasing function under glucose stimulation of mouse islets, and outcomes of syngeneic murine islet transplantation with systemic DLS administration. DLS treatment promoted insulin production and suppressed somatostatin production, suggesting that cancelation of the binding between ghrelin and GHS-R1a on β or δ cells improved insulin expression. DLS also promoted the glucose-dependent insulin-releasing function of β cells. However, the therapeutic effect of DLS in islet transplantation was fractional. In conclusion, the GHS-R1a antagonist showed preferable effects in improving the therapeutic outcomes of islet transplantation, including the promotion of insulin-releasing function.

| S-EPMC8553779 | biostudies-literature

Development of a [<sup>68</sup>Ga]-ghrelin analogue for PET imaging of the ghrelin receptor (GHS-R1a).

Project description:The ghrelin receptor is a member of the growth hormone secretagogue receptor (GHS-R) family and is present at low concentrations in tissues such as the brain, kidney, cardiovascular system, and prostate. The ghrelin receptor plays an important role in cellular proliferation, apoptosis, invasion, and migration associated with the progression of many cancers, including prostate, breast, ovarian, testicular, and intestinal carcinomas. Ghrelin, the endogenous ligand, is a 28 amino acid peptide (IC50 = 3.1 nM) known to have poor in vivo stability. Herein, we report the synthesis and evaluation of [Dpr3(octanoyl),Lys19(Ga-DOTA)]ghrelin(1-19). This new ghrelin analogue has a binding affinity (IC50 = 5.9 nM) comparable to that of natural ghrelin. Preliminary in vivo evaluation shows higher uptake of [Dpr3(octanoyl),Lys19(68Ga-DOTA)]ghrelin(1-19) in HT1080/GHSR-1a xenografts than the non-transfected HT1080 xenografts in NOD-SCID mice, although considerable uptake is observed in the kidneys. This is the first example of ghrelin receptor PET imaging in a xenograft model using a peptide derived directly from the endogenous ligand and serves as motivation for developing more effective ghrelin-based radiopeptides.

| S-EPMC6194486 | biostudies-literature

The Role of Ghrelin/GHS-R1A Signaling in Nonalcohol Drug Addictions.

Project description:Drug addiction causes constant serious health, social, and economic burden within the human society. The current drug dependence pharmacotherapies, particularly relapse prevention, remain limited, unsatisfactory, unreliable for opioids and tobacco, and even symptomatic for stimulants and cannabinoids, thus, new more effective treatment strategies are researched. The antagonism of the growth hormone secretagogue receptor type A (GHS-R1A) has been recently proposed as a novel alcohol addiction treatment strategy, and it has been intensively studied in experimental models of other addictive drugs, such as nicotine, stimulants, opioids and cannabinoids. The role of ghrelin signaling in these drugs effects has also been investigated. The present review aims to provide a comprehensive overview of preclinical and clinical studies focused on ghrelin's/GHS-R1A possible involvement in these nonalcohol addictive drugs reinforcing effects and addiction. Although the investigation is still in its early stage, majority of the existing reviewed experimental results from rodents with the addition of few human studies, that searched correlations between the genetic variations of the ghrelin signaling or the ghrelin blood content with the addictive drugs effects, have indicated the importance of the ghrelin's/GHS-R1As involvement in the nonalcohol abused drugs pro-addictive effects. Further research is necessary to elucidate the exact involved mechanisms and to verify the future potential utilization and safety of the GHS-R1A antagonism use for these drug addiction therapies, particularly for reducing the risk of relapse.

| S-EPMC8776007 | biostudies-literature

High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs.

Project description:Despite its central role in signaling and the potential therapeutic applications of inverse agonists, the molecular mechanisms underlying G protein-coupled receptor (GPCR) constitutive activity remain largely to be explored. In this context, ghrelin receptor GHS-R1a is a peculiar receptor in the sense that it displays a strikingly high, physiologically relevant, constitutive activity. To identify the molecular mechanisms responsible for this high constitutive activity, we have reconstituted a purified GHS-R1a monomer in a lipid disc. Using this reconstituted system, we show that the isolated ghrelin receptor per se activates G(q) in the absence of agonist, as assessed through guanosine 5'-O-(thiotriphosphate) binding experiments. The measured constitutive activity is similar in its extent to that observed in heterologous systems and in vivo. This is the first direct evidence for the high constitutive activity of the ghrelin receptor being an intrinsic property of the protein rather than the result of influence of its cellular environment. Moreover, we show that the isolated receptor in lipid discs recruits arrestin-2 in an agonist-dependent manner, whereas it interacts with ?-AP2 in the absence of ligand or in the presence of ghrelin. Of importance, these differences are linked to ligand-specific GHS-R1a conformations, as assessed by intrinsic fluorescence measurements. The distinct ligand requirements for the interaction of purified GHS-R1a with arrestin and AP2 provide a new rationale to the differences in basal and agonist-induced internalization observed in cells.

| S-EPMC3281683 | biostudies-literature

Ghrelin uses the GHS-R1a/Gi/cAMP pathway and induces differentiation only in mature osteoblasts. This ghrelin pathway is impaired in AIS patients.

Project description:We have examined the Acylated Ghrelin (AG)/Gi pathway in different human osteoblastic cell lines. We have found that: 1) AG induces differentiation/mineralization only in mature osteoblasts; 2) the expression of GHS-R1a increases up to the mature cell stage, 3) the action is mediated via the GHS-R/Gi/cAMP pathway only in mature osteoblasts, and 4) osteoblastic cells from adolescent idiopathic scoliosis (AIS) are resistant to the AG/Gi/cAMP pathway. Altogether, these results suggested that AG uses the GHS-R1a/Gi/cAMP pathway to induce differentiation in mature osteoblasts only. This pathway is impaired in AIS osteoblasts. Understanding AG-specific pathways involved in normal and pathological osteoblasts may be useful for developing new treatments for pathologies such as AIS or osteoporosis.

| S-EPMC7494670 | biostudies-literature

Ghrelin stimulation of growth hormone-releasing hormone neurons is direct in the arcuate nucleus.

Project description:BACKGROUND:Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin. PRINCIPAL FINDINGS:Here, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by gamma-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate. CONCLUSION:Thus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.

| S-EPMC2820089 | biostudies-literature

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema.

Project description:Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na(+) transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na(+)/K(+)-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na(+) uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema.

| S-EPMC3277580 | biostudies-literature

Growth hormone-releasing hormone agonist attenuates vascular calcification in diabetic db/db mice.

Project description:IntroductionVascular calcification (VC) is an independent risk factor for cardiovascular diseases. VC increases mortality of all-causes. VC is one of most common cardiovascular complications in type II diabetes. So far, no therapy has been proven to be effective in treatment of clinical VC. The present study investigated the therapeutic effects of MR409, an agonistic analog of growth hormone-releasing hormone (GHRH-A), on VC in diabetic db/db mice.Method and resultDiabetic mice were injected with MR409 subcutaneously every day for 8 weeks. Long-term treatment with MR409 improved serum lipid profile and endothelium-dependent relaxation to acetylcholine, and reduced vascular structural injury in diabetic mice without affecting serum growth hormone level. Echocardiography showed that calcium plaques present in heart valve of diabetic mice disappeared in diabetic mice after treatment with MR409. MR409 inhibited vascular calcium deposition associated with a marked reduction in the expressions of osteogenic-regulated alkaline phosphatase (ALP) and transcription osteogenic marker gene Runx2 in diabetic mice. MR409 also inhibited vascular reactive oxygen species (ROS) generation and upregulated the expressions of anti-calcifying protein Klotho in diabetic mice.DiscussionOur results demonstrate that GHRH-A MR409 can effectively attenuate VC and heart valve calcification, and protect against endothelial dysfunction and vascular injury in diabetic mice without significantly affecting pituitary-growth hormone axis. The mechanisms may involve upregulation of anti-calcifying protein Klotho and reduction in vascular ROS and the expression of redox sensitive osteogenic genes Runx2 and ALP. GHRH-A may represent a new pharmacological strategy for treatment of VC and diabetics associated cardiovascular complications.

| S-EPMC9889365 | biostudies-literature

Cardioprotective effects of growth hormone-releasing hormone agonist after myocardial infarction.

Project description:Whether the growth hormone (GH)/insulin-like growth factor 1(IGF-1) axis exerts cardioprotective effects remains controversial; and the underlying mechanism(s) for such actions are unclear. Here we tested the hypothesis that growth hormone-releasing hormone (GHRH) directly activates cellular reparative mechanisms within the injured heart, in a GH/IGF-1 independent fashion. After experimental myocardial infarction (MI), rats were randomly assigned to receive, during a 4-week period, either placebo (n = 14), rat recombinant GH (n = 8) or JI-38 (n = 8; 50 microg/kg per day), a potent GHRH agonist. JI-38 did not elevate serum levels of GH or IGF-1, but it markedly attenuated the degree of cardiac functional decline and remodeling after injury. In contrast, GH administration markedly elevated body weight, heart weight, and circulating GH and IGF-1, but it did not offset the decline in cardiac structure and function. Whereas both JI-38 and GH augmented levels of cardiac precursor cell proliferation, only JI-38 increased antiapoptotic gene expression. The receptor for GHRH was detectable on myocytes, supporting direct activation of cardiac signal transduction. Collectively, these findings demonstrate that within the heart, GHRH agonists can activate cardiac repair after MI, suggesting the existence of a potential signaling pathway based on GHRH in the heart. The phenotypic profile of the response to a potent GHRH agonist has therapeutic implications.

| S-EPMC2823907 | biostudies-other

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