Ghrelin Receptor

Els, Sylvia; Beck‐Sickinger, Annette G.; Chollet, Constance

doi:10.1016/b978-0-12-381296-4.00006-3

Cited by 49 publications

(27 citation statements)

References 29 publications

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“…SP-analogue was reported as a potent inverse agonist for the GHS-R1a receptor attenuating its high ligand independent basal activity [37]. Consequently, exposure to SP-analogue has been shown to significantly increase membrane GHS-R1a receptor expression and sensitize receptor signalling [38], [39]. Calcium increase was not significant different following exposure to H. procumbens root extract concentrations at the lowest concentrations (0.25 and 0.125 mg/mL) of SP-analogue pre-treatment.…”

Section: Resultsmentioning

confidence: 99%

Devil's Claw to Suppress Appetite—Ghrelin Receptor Modulation Potential of a Harpagophytum procumbens Root Extract

et al. 2014

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Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.

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Section: Resultsmentioning

confidence: 99%

Devil's Claw to Suppress Appetite—Ghrelin Receptor Modulation Potential of a Harpagophytum procumbens Root Extract

et al. 2014

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“…The signal transduction assay was performed as previously described 40,41 . Briefly, COS-7 cells (obtained from American Type Culture Collection) were seeded into 48-well plates and were transiently co-transfected with wild-type receptor or receptor mutant and a chimeric G protein (G αΔ6qi4myr ) plasmid DNA 42 .…”

Section: Methodsmentioning

confidence: 99%

Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor

Yang

Han

Keller

et al. 2018

Nature

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108

213

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Neuropeptide Y (NPY) receptors belong to the G protein-coupled receptor (GPCR) superfamily and play important roles in food intake, anxiety and cancer regulation1,2. The NPY/Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in mammals, namely Y1, Y2, Y4 and Y5 receptors, with different affinity and selectivity3. NPY is the most powerful stimulant of food intake and this effect is primarily mediated by Y1 receptor (Y1R)4. A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity4, tumor1 and bone loss5. However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability6. Here we report crystal structures of the human Y1R bound to two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal binding modes of Y1R to several structurally diverse antagonists and determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance (NMR), photo-crosslinking and functional studies, provide insights into the binding behavior of the agonist and for the first time determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery targeting NPY receptors.

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“…35 Coupling of distinct amino acids and palmitic acid was performed manually with 5 equiv Fmoc amino acid, 5 equiv DIC and 5 equiv HOBt in DMF. PEG2 was coupled with 3 equiv MeO-PEG2-NHS, 6 equiv DIC and DMAP in DCM.…”

Section: Peptide Synthesismentioning

confidence: 99%