Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+

Ray, Kausik K.; Tisdale, Justin; Dodd, Robert H.; Dauban, Philippe; Ruat, Martial; Northup, John K.

doi:10.1074/jbc.m506681200

Cited by 51 publications

(28 citation statements)

References 33 publications

(57 reference statements)

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“…Under these conditions, maximal responses to all compounds were further reduced; however, the potencies were not significantly different from the potencies at ⌬N CaSRs in the presence of extracellular Ca 2ϩ . These results are in agreement with previous studies suggesting that CaSRs may contain more than one Ca 2ϩ -binding site (Ray et al, 2005) and indicate that both classes of compounds interact with the transmembrane domains of CaSRs and both have intrinsic agonist activity, but AC-265347 and (S)-AC-265347 have greater intrinsic activity than the phenylalkylamine calcimimetics.…”

Section: Resultssupporting

confidence: 92%

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Nong

Owens²,

Gustafsson³

et al. 2011

J Pharmacol Exp Ther

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Section: Resultssupporting

confidence: 92%

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Nong

Owens²,

Gustafsson³

et al. 2011

J Pharmacol Exp Ther

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“…Whereas the chimeric receptor Gly-link9ins with an insertion of a nine-amino acid long random coil Gly-peptide expressed poorly at the cell surface, by selecting a stably transformed clone of HEK293 that expressed sufficient Gly-link9ins receptor, we found no response to [Ca 2ϩ ] o but activation by the allosteric agonist NPS-R568 alone or in combination with Ca 2ϩ . This phenotype mimics what we have previously reported for an ECD-deleted construct, T903-Rhoc, which revealed the 7TMD sites for two positive allosteric agonists NPS-R568 and Calindol and also for Ca 2ϩ (15,21). These results suggest that [Ca 2ϩ ] o -activated VFTM of the Gly-link9ins mutant receptor did not transmit the activation signal to the 7TMD for G-protein signaling.…”

Section: Discussionsupporting

confidence: 87%

Elucidation of the Role of Peptide Linker in Calcium-sensing Receptor Activation Process

Ray

Adipietro

Chen

et al. 2007

Journal of Biological Chemistry

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Family 3 G-protein-coupled receptors (GPCRs), which includes metabotropic glutamate receptors (mGluRs), sweet and "umami" taste receptors (T1Rs), and the extracellular calcium-sensing receptor (CaR), represent a distinct group among the superfamily of GPCRs characterized by large amino-terminal extracellular ligand-binding domains (ECD) with homology to bacterial periplasmic amino acid-binding proteins that are responsible for signal detection and receptor activation through as yet unresolved mechanism(s) via the seven-transmembrane helical domain (7TMD) common to all GPCRs. To address the mechanism(s) by which ligand-induced conformational changes are conveyed from the ECD to the 7TMD for G-protein activation, we altered the length and composition of a 14-amino acid linker segment common to all family 3 GPCRs except GABA B receptor, in the CaR by insertion, deletion, and site-directed mutagenesis of specific highly conserved residues. Small alterations in the length and composition of the linker impaired cell surface expression and abrogated signaling of the chimeric receptors. The exchange of nine amino acids within the linker of CaR with the homologous sequence of mGluR1, however, preserved receptor function. Ala substitution for the four highly conserved residues within this amino acid sequence identified a Leu at position 606 of the CaR critical for cell surface expression and signaling. Substitution of Leu 606 for Ala resulted in impaired cell surface expression. However, Ile and Val substitutions displayed strong activating phenotypes. Disruption of the linker by insertion of nine amino acids of a random-coiled structure uncoupled the ECD from regulating the 7TMD. These data are consistent with a model of receptor activation in which the peptide linker, and particularly Leu 606 , provides a critical interaction for the CaR signal transmission, a finding likely to be relevant for all family 3 GPCRs containing this conserved motif.

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“…The present data also confirm the CaSR as the mediator of the Ca 21 e relaxation responses, as calindol, a CaSR agonist, enhanced while Calhex 231, a calcilytic at the receptor, reduced relaxation of PE-contracted arteries in a concentrationdependent manner. Both compounds bind to the allosteric site of the CaSR to increase or reduce Ca 21 sensitivity (Kessler et al, 2004;Ray et al, 2005;Weston et al, 2005;Ciceri et al, 2012 ] e -response curves were generated from tracing data obtained in tissues from C57BL/6 (B), nNOS 2/2 (C), and eNOS 2/2 (D) mice mounted in PSS with 1 mM CaCl 2 . L-NIO had a larger effect in tissues from C57BL/6 and nNOS 2/2 mice than those from eNOS 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

Nitric-Oxide Synthase Knockout Modulates Ca²⁺-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries

Awumey¹,

Bridges²,

Williams³

et al. 2013

J Pharmacol Exp Ther

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Extracellular calcium (Ca 21 e )-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries is dependent on an intact perivascular sensory nerve network that expresses the Ca 21 -sensing receptor (CaSR). Activation of the receptor stimulates an endocannabinoid vasodilator pathway, which is dependent on cytochrome P450 and phospholipase A 2 but largely independent of the endothelium. In the present study, we determined the role of nitric oxide (NO) in perivascular nerve CaSR-mediated relaxation of PE-contracted mesenteric resistance arteries isolated from mice. Using automated wire myography, we studied the effects of NO synthase (NOS) gene knockout (NOS 2/2 ) and pharmacologic inhibition of NOS on Ca mice. 7-Nitroindazole had no significant effect on relaxation of arteries from NOS 2/2 mice, but both N G -nitro-L-arginine methylester and N G -monomethyl-L-arginine significantly reduced the relaxation maxima in all groups. Interestingly, the nNOS-selective inhibitor S-methyl-L-thiocitrulline significantly increased the EC 50 value by 60% in tissues from C57BL/6 mice but reduced the maximum response by 80% in those from nNOS 2/2 mice. Ca 21 -activated big potassium channels play a major role in the process, as demonstrated by the effect of iberiotoxin. We conclude that CaSR signaling in mesenteric arteries stimulates eNOS and NO production that regulates Ca 21 e -induced relaxation.

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Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+

Cited by 51 publications

References 33 publications

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Elucidation of the Role of Peptide Linker in Calcium-sensing Receptor Activation Process

Nitric-Oxide Synthase Knockout Modulates Ca²⁺-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries

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Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+

Cited by 51 publications

References 33 publications

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Characterization of Highly Efficacious Allosteric Agonists of the Human Calcium-Sensing Receptor

Elucidation of the Role of Peptide Linker in Calcium-sensing Receptor Activation Process

Nitric-Oxide Synthase Knockout Modulates Ca2+-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries

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Nitric-Oxide Synthase Knockout Modulates Ca²⁺-Sensing Receptor Expression and Signaling in Mouse Mesenteric Arteries