Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity

Chu, Kit Man; Chow, Kevin B.S.; Leung, Po Ki; Lau, Pui Ngan; Chan, Chi Bun; Chen, Cheng; Wise, Helen

doi:10.1016/j.biocel.2006.11.007

Cited by 44 publications

(25 citation statements)

References 45 publications

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“…Peptides were tested in COS7 cells, either transiently or stably transfected with the ghrelin receptor. EC 50 values and efficacy of peptides tested with the stable or transiently tranfected cells were comparable. COS7 cells were grown in a humidified atmosphere at 37°C and 5% CO 2 in Dulbecco's modified Eagle's medium with higher glucose supplemented with 10% (v/v) FCS and 1% (v/v) penicillin/streptomycin.…”

Section: ■ Materials and Methodsmentioning

confidence: 72%

An Aromatic Region To Induce a Switch between Agonism and Inverse Agonism at the Ghrelin Receptor

et al. 2012

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The ghrelin receptor displays a high constitutive activity suggested to be involved in the regulation of appetite and food intake. Here, we have created peptides with small changes in the core binding motif -wFw- of the hexapeptide KwFwLL-NH(2) that can swap the peptide behavior from inverse agonism to agonism, indicating the importance of this sequence. Introduction of β-(3-benzothienyl)-d-alanine (d-Bth), 3,3-diphenyl-d-alanine (d-Dip) and 1-naphthyl-d-alanine (d-1-Nal) at position 2 resulted in highly potent and efficient inverse agonists, whereas the substitution of d-tryptophane at position 4 with 1-naphthyl-d-alanine (d-1-Nal) and 2-naphthyl-d-alanine (d-2-Nal) induces agonism in functional assays. Competitive binding studies showed a high affinity of the inverse agonist K-(d-1-Nal)-FwLL-NH(2) at the ghrelin receptor. Moreover, mutagenesis studies of the receptor revealed key positions for the switch between inverse agonist and agonist response. Hence, only minor changes in the peptide sequence can decide between agonism and inverse agonism and have a major impact on the biological activity.

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Section: ■ Materials and Methodsmentioning

confidence: 72%

An Aromatic Region To Induce a Switch between Agonism and Inverse Agonism at the Ghrelin Receptor

et al. 2012

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“…GHSR1b is not activated by ghrelin, but paradoxically, is expressed in many tumours, including breast, prostate, adrenal and lung cancers, where it is often expressed at higher levels than the GHSR1a isoform [18,20,22,24,60]. As GHSR1b does not bind ghrelin, its primary role may be as a modulator of other G proteincoupled receptors (GPCRs) by increasing internalisation of GHSR1a [61][62][63] and by forming novel GPCR combinations by heterodimerisation [24]. Deducing the receptor(s) and signalling pathways for ghrelin as well as the role of GHSR1b in endometrial cancer are most important future studies.…”

Section: Discussionmentioning

confidence: 98%

Expression and In Vitro Functions of the Ghrelin Axis in Endometrial Cancer

et al. 2010

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Ghrelin is a peptide hormone produced in the stomach and a range of other tissues, where it has endocrine, paracrine and autocrine roles in both normal and disease states. Ghrelin has been shown to be an important growth factor for a number of tumours, including prostate and breast cancers. In this study, we examined the expression of the ghrelin axis (ghrelin and its receptor, the growth hormone secretagogue receptor, GHSR) in endometrial cancer. Ghrelin is expressed in a range of endometrial cancer tissues, while its cognate receptor, GHSR1a, is expressed in a small subset of normal and cancer tissues. Low to moderately invasive endometrial cancer cell lines were examined by RT-PCR and immunoblotting, demonstrating that ghrelin axis mRNA and protein expression correlate with differentiation status of Ishikawa, HEC1B and KLE endometrial cancer cell lines. Moreover, treatment with ghrelin potently stimulated cell proliferation and inhibited cell death. Taken together, these data indicate that ghrelin promotes the progression of endometrial cancer cells in vitro, and may contribute to endometrial cancer pathogenesis and represent a novel treatment target.

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“…However, recently, the GHS-R1a receptor has also been shown to heterodimerize with other GPCRs involved in appetite regulation and food reward (for review see 19 ), including its truncated splice variant, the GHS-R1b receptor 18,[20][21][22] , the melanocortin 3 receptor (MC3) and the dopamine receptors (D1 and D2) [23][24][25][26][27] . Moreover, our lab has demonstrated compelling evidence for a functional interaction between the GHS-R1a and the 5-HT2C receptor 27 .…”

Section: Introductionmentioning

confidence: 99%

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Schellekens¹,

Francesco²,

Kandil³

et al. 2015

ACS Chem. Neurosci.

107

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Understanding the intricate pathways modulating appetite and subsequent food intake is of particular importance considering the rise in obesity incidence across the globe. The serotonergic system, specifically the 5-HT2C receptor, has shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor wellknown for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signalling is not due to coupling to GαS, as no increase in cAMP signalling is observed. Next, flowcytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor.In addition, we demonstrate co-localized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic-and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signalling is blocked, ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into biological significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management. ACS Paragon Plus Environment ACS Chemical Neuroscience 5

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Over-expression of the truncated ghrelin receptor polypeptide attenuates the constitutive activation of phosphatidylinositol-specific phospholipase C by ghrelin receptors but has no effect on ghrelin-stimulated extracellular signal-regulated kinase 1/2 activity

Cited by 44 publications

References 45 publications

An Aromatic Region To Induce a Switch between Agonism and Inverse Agonism at the Ghrelin Receptor

An Aromatic Region To Induce a Switch between Agonism and Inverse Agonism at the Ghrelin Receptor

Expression and In Vitro Functions of the Ghrelin Axis in Endometrial Cancer

Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

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