Allosteric Modulation of the Calcium-sensing Receptor by γ-Glutamyl Peptides

Broadhead, Geoffrey; Mun, Hee-Chang; Avlani, Vimesh Ashvinkumar; Jourdon, Orane; Church, W. Bret; Christopoulos, Arthur; Delbridge, Leigh; Conigrave, Arthur D.

doi:10.1074/jbc.m110.149724

Cited by 87 publications

(27 citation statements)

References 47 publications

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“…These findings were consistent with reports by Wang et al and Broadhead et al, in which the importance of the interaction between both N- terminal amino acid and the C-terminal carboxyl groups of γ-glutamyl tripeptides and the active site of the CaSR was discussed. 5,6) Figure 2 shows the putative interaction between 35 and the CaSR, where the VFD mediates 35. The following three interactions must occur between γ-glutamyl peptides and the VFD of CaSR: γ-L-glutamyl residue with a zwitterionic binding site, which has an amino acid binding site for VFD; hydrophobic side chain of Val with a hydrophobic interaction site; and Cterminal carboxylic acid of glycine with an ionic binding site.…”

Section: Resultsmentioning

confidence: 99%

“…3,4) γ-Glutamyl peptides have also been reported to bind to the large extracellular VFD of CaSR. 5,6) Previously, in a preliminary hCaSR functional assay of γ-glutamyl dipeptides and γ-glutamyl tripeptides comprising proteinogenic amino acids, we identified various γ-glutamyl peptides, including 36 and γ-glutamylvalylglycine (γ-Glu-Val-Gly, 35), as CaSR agonists. 7) As the agonist peptides contain an N-terminal γ-L-glutamyl residue comprising α-amino and α-carboxyl groups, as with amino acids, it is reasonable to assume that peptides containing such a unit will bind to and activate the CaSR.…”

Section: Structure-casr-activity Relation Of Kokumi γ-Glutamyl Peptidesmentioning

confidence: 99%

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Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

et al. 2016

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Modulation of the calcium sensing receptor (CaSR) is one of the physiological activities of γ-glutamyl peptides such as glutathione (γ-glutamylcysteinylglycine). γ-Glutamyl peptides also possess a flavoring effect, i.e., sensory activity of kokumi substances, which modifies the five basic tastes when added to food. These activities have been shown to be positively correlated, suggesting that kokumi γ-glutamyl peptides are perceived through CaSRs in humans. Our research is based on the hypothesis that the discovery of highly active CaSR agonist peptides will lead to the creation of practical kokumi peptides. Through continuous study of the structure-CaSR-activity relation of a large number of γ-glutamyl peptides, we have determined that the structural requirements for intense CaSR activity of γ-glutamyl peptides are as follows: existence of an N-terminal γ-L-glutamyl residue; existence of a moderately sized, aliphatic, neutral substituent at the second residue in an L-configuration; and existence of a C-terminal carboxylic acid, preferably with the existence of glycine as the third constituent. By the sensory analysis of γ-glutamyl peptides selected by screening using the CaSR activity assay, γ-glutamylvalylglycine was found to be a potent kokumi peptide. Furthermore, norvaline-containing γ-glutamyl peptides, i.e., γ-glutamylnorvalylglycine and γ-glutamylnorvaline, possessed excellent sensory activity of kokumi substances. A novel, practical industrial synthesis of regiospecific γ-glutamyl peptides is also required for their commercialization, which was achieved through the ring opening reaction of N-α-carbobenzoxy-L-glutamic anhydride and amino acids or peptides in the presence of Nhydroxysuccinimide.

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Section: Resultsmentioning

confidence: 99%

Section: Structure-casr-activity Relation Of Kokumi γ-Glutamyl Peptidesmentioning

confidence: 99%

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

et al. 2016

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“…The CaSR is a G-protein couple-receptor and activation of the CaSR has been shown to inhibit adenylate cyclase and to decrease cAMP generation [23,24]. Since the 50-pS K channels were stimulated by cAMP [18], we examined whether the effect of raising the external Ca 2+ on the 50-pS K channel was the result of decreasing cAMP Figure 7 is a recording showing the effect of 3 mM Ca 2+ on the basolateral 50-pS K channels in the presence of 100μM dibutyryl-cAMP (db-cAMP.)…”

Section: Resultsmentioning

confidence: 99%

Stimulation of Ca2+-sensing receptor inhibits the basolateral 50-pS K channels in the thick ascending limb of rat kidney

Kong

Zhang

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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We used the patch-clamp technique to study the effect of changing the external Ca2+ on the basolateral 50-pS K channel in the thick ascending limb (TAL) of rat kidney. Increasing the external Ca2+ concentration from 1 mM to 2 or 3 mM inhibited the basolateral 50 −pS K channels while decreasing external Ca2+ to 10 μM increased the 50-pS K channel activity. The effect of the external Ca2+ on the 50-pS K channels was observed only in cell-attached patches but not in excised patches. Moreover, the inhibitory effect of increasing external Ca2+ on the 50-pS K channels was absent in the presence of NPS2390, an antagonist of Ca2+-sensing receptor (CaSR), suggesting that the inhibitory effect of the external Ca2+ was the result of stimulation of the CaSR. Application of the membrane-permeable cAMP analogue increased the 50-pS K channel activity but did not block the effect of raising the external Ca2+ on the K channels. Neither inhibition of phospholipase A2 (PLA2) nor suppression of cytochrome P450-ω-hydroxylation-dependent metabolism of arachidonic acid was able to abolish the effect of raising the external Ca2+ on the 50-pS K channels. In contrast, inhibition of phospholipase C (PLC) or blocking protein kinase C (PKC) completely abolished the inhibition of the basolateral 50-pS K channels induced by raising the external Ca2+. We conclude that the external Ca2+ concentration plays an important role in the regulation of the basolateral K channel activity in the TAL and that the effect of the external Ca2+ is mediated by the CaSR which stimulates PLC-PKC pathways. The regulation of the basolateral K channels by the CaSR may be the mechanism by which extracellular Ca2+ level modulates the reabsorption of divalent cations.

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“…The CaSR regulates the blood-mineral ion balance largely by regulating parathyroid hormone secretion by the parathyroid gland, calcitonin secretion by the thyroid gland, Ca 2ϩ excretion by the kidneys, and osteoblast proliferation and differentiation (2)(3)(4). In addition to activation by Ca 2ϩ ions, the CaSR is also activated or potentiated by a variety of compounds, including other di-and trivalent cations, polyamines such as spermine, aminoglycosides, as well as other physiologically relevant molecules including L-amino acids and ␥-glutamyl peptides (including glutathione), and pharmacologically important phenylalkylamine calcimimetics such as cinacalcet and NPS R-568 (1,(5)(6)(7)(8).…”

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confidence: 99%

Calcium-sensing Receptor Modulates Cell Adhesion and Migration via Integrins

Tharmalingam

Daulat

Antflick

et al. 2011

Journal of Biological Chemistry

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Background:The calcium-sensing receptor (CaSR) is a nutrient sensor implicated in cell migration. Results:The CaSR is present in a signaling complex with ␤1-containing integrins. Conclusion:The results demonstrate that an ion-sensing G protein-coupled receptor couples to the integrins to promote cellular adhesion and migration in tumor cells. Significance: Identifying components of the CaSR signaling complex is important for understanding the role of the CaSR in cancer cell metastasis.

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Allosteric Modulation of the Calcium-sensing Receptor by γ-Glutamyl Peptides

Abstract: ␥-Glutamyl peptides were identified previously as novel positive allosteric modulators of Ca

Cited by 87 publications

References 47 publications

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

Structure–CaSR–Activity Relation of <i>Kokumi</i> γ-Glutamyl Peptides

Stimulation of Ca2+-sensing receptor inhibits the basolateral 50-pS K channels in the thick ascending limb of rat kidney

Calcium-sensing Receptor Modulates Cell Adhesion and Migration via Integrins

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