scholarly journals Calcium-sensing receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Daniel Bikle ◽  
Hans Bräuner-Osborne ◽  
Edward M. Brown ◽  
Wenhan Chang ◽  
Arthur Conigrave ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ionic Strength ◽  
Receptor Activation ◽  
Extracellular Ph ◽  
Allosteric Modulators ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Trivalent Cations ◽  
Amino Acid Binding ◽  
Peptide Analogues

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [44]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [74]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 106], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [34, 44, 58, 104, 105]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [143, 51]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [105]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

scholarly journals Calcium-sensing receptor in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Daniel Bikle ◽  
Hans Bräuner-Osborne ◽  
Edward M. Brown ◽  
Wenhan Chang ◽  
Arthur Conigrave ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ionic Strength ◽  
Receptor Activation ◽  
Extracellular Ph ◽  
Allosteric Modulators ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Trivalent Cations ◽  
Amino Acid Binding ◽  
Peptide Analogues

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [47] and subsequently updated [77]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [78]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 110], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [36, 47, 61, 108, 109]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [148, 54]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [18] or decreased extracellular ionic strength [109]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

scholarly journals Calcium-sensing receptor (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

2020 ◽  
Vol 2020 (5) ◽  
Author(s):  
Daniel Bikle ◽  
Hans Bräuner-Osborne ◽  
Edward M. Brown ◽  
Wenhan Chang ◽  
Arthur Conigrave ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ionic Strength ◽  
Receptor Activation ◽  
Extracellular Ph ◽  
Allosteric Modulators ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Trivalent Cations ◽  
Amino Acid Binding ◽  
Peptide Analogues

The calcium-sensing receptor (CaS, provisional nomenclature as recommended by NC-IUPHAR [46] and subsequently updated [76]) responds to multiple endogenous ligands, including extracellular calcium and other divalent/trivalent cations, polyamines and polycationic peptides, L-amino acids (particularly L-Trp and L-Phe), glutathione and various peptide analogues, ionic strength and extracellular pH (reviewed in [77]). While divalent/trivalent cations, polyamines and polycations are CaS receptor agonists [14, 109], L-amino acids, glutamyl peptides, ionic strength and pH are allosteric modulators of agonist function [35, 46, 60, 107, 108]. Indeed, L-amino acids have been identified as "co-agonists", with both concomitant calcium and L-amino acid binding required for full receptor activation [147, 53]. The sensitivity of the CaS receptor to primary agonists is increased by elevated extracellular pH [17] or decreased extracellular ionic strength [108]. This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

scholarly journals Illuminating the allosteric modulation of the calcium-sensing receptor

2020 ◽  
Vol 117 (35) ◽  
pp. 21711-21722
Author(s):  
Hongkang Liu ◽  
Ping Yi ◽  
Wenjing Zhao ◽  
Yuling Wu ◽  
Francine Acher ◽  
...  
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Membrane Receptors ◽  
Allosteric Modulators ◽  
Active Conformation ◽  
Calcium Sensing Receptor ◽  
Single Receptor ◽  
Calcium Sensing

Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response.

scholarly journals Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan

Cell Research ◽  
2021 ◽  
Author(s):  
Shenglong Ling ◽  
Pan Shi ◽  
Sanling Liu ◽  
Xianyu Meng ◽  
Yingxin Zhou ◽  
...  
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Bound States ◽  
Close Contact ◽  
Receptor Activation ◽  
Active State ◽  
Structural Level ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Class C

AbstractThe human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.

scholarly journals Calcium Sensing Receptor Activation by a Calcimimetic Suggests a Link between Cooperativity and Intracellular Calcium Oscillations

2002 ◽  
Vol 277 (51) ◽  
pp. 49691-49699 ◽  
Author(s):  
Susanne Miedlich ◽  
Lucio Gama ◽  
Gerda E. Breitwieser
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Intracellular Calcium ◽  
Receptor Activation ◽  
Calcium Oscillations ◽  
Calcium Stores ◽  
Calcium Sensing Receptor ◽  
Hek 293 ◽  
Calcium Sensing ◽  
Intracellular Ca

Activation of the calcium sensing receptor (CaR) by small increments in extracellular calcium (Ca2+e) induces intracellular calcium (Ca2+i) oscillations that are dependent on thapsigargin-sensitive intracellular calcium stores. Phenylalkylamines such as NPS R-568 are allosteric modulators (calcimimetics) that activate CaR by increasing the apparent affinity of the receptor for calcium. We determined, by fluorescence imaging with fura-2, whether the calcimimetic NPS R-568 could activate Ca2+ioscillations in HEK-293 cells expressing human CaR. NPS R-568 was more potent than Ca2+eat eliciting Ca2+ioscillations, particularly at low [Ca2+]e(as low as 0.1 mm). The oscillation frequencies elicited by NPS R-568 varied over a 2-fold range from peak to peak intervals of 60–70 to 30–45 s, depending upon the concentrations of both Ca2+eand NPS R-568. Finally, NPS R-568 induced sustained (>15 min after drug removal) Ca2+ioscillations, suggesting slow release of the drug from its binding site. We exploited the potency of NPS R-568 for eliciting Ca2+ioscillations for structural studies. Truncation of the CaR carboxyl terminus from 1077 to 886 amino acids had no effect on the ability of Ca2+or NPS R-568 to induce Ca2+ioscillations, but further truncation (to 868 amino acids) eliminated both highly cooperative Ca2+-dependent activation and regular Ca2+ioscillations. Alanine scanning within the amino acid sequence from Arg873to His879reveals a linkage between the cooperativity for Ca2+-dependent activation and establishment and maintenance of intracellular Ca2+oscillations. The amino acid residues critical to both functions of CaR may contribute to interactions with either G proteins or between CaR monomers within the functional dimer.

408 Aromatic amino acids alleviate intestinal inflammation in piglets through calcium-sensing receptor activation

2017 ◽  
Vol 95 (suppl_4) ◽  
pp. 201-202 ◽  
Author(s):  
B. Tan ◽  
B. Huang ◽  
J. Wang ◽  
G. P. Guang ◽  
C. B. Yang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Intestinal Inflammation ◽  
Aromatic Amino Acids ◽  
Receptor Activation ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretionviaa Histidine-Independent Mechanism

2015 ◽  
Vol 26 (9) ◽  
pp. 2163-2171 ◽  
Author(s):  
Katherine L. Campion ◽  
Wanda D. McCormick ◽  
Jim Warwicker ◽  
Mohd Ezuan Bin Khayat ◽  
Rebecca Atkinson-Dell ◽  
...  
Keyword(s):  
Extracellular Ph ◽  
Receptor Activity ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Independent Mechanism

scholarly journals Epithelial calcium–sensing receptor activation by eosinophil granule protein analog stimulates collagen matrix contraction

2012 ◽  
Vol 73 (1-4) ◽  
pp. 414-419 ◽  
Author(s):  
Peter D. Ngo ◽  
R. John MacLeod ◽  
Vince Mukkada ◽  
Razan Turki ◽  
Glenn T. Furuta
Keyword(s):  
Collagen Matrix ◽  
Receptor Activation ◽  
Calcium Sensing Receptor ◽  
Granule Protein ◽  
Calcium Sensing ◽  
Eosinophil Granule ◽  
Matrix Contraction

scholarly journals Calcium-Sensing Receptor Activation Increases Cell-Cell Adhesion and ß-Cell Function

2012 ◽  
Vol 30 (3) ◽  
pp. 575-586 ◽  
Author(s):  
Claire E. Hills ◽  
Mustafa Y.G. Younis ◽  
Jeanette Bennett ◽  
Eleftherios Siamantouras ◽  
Kuo-Kang Liu ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Function ◽  
Receptor Activation ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Cell Cell

scholarly journals Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity

2018 ◽  
Vol 175 (21) ◽  
pp. 4095-4108 ◽  
Author(s):  
Natalie A Diepenhorst ◽  
Katie Leach ◽  
Andrew N Keller ◽  
Patricia Rueda ◽  
Anna E Cook ◽  
...  
Keyword(s):  
Allosteric Modulators ◽  
Calcium Sensing Receptor ◽  
Osteoclast Activity ◽  
Calcium Sensing ◽  
Human Osteoclast ◽  
Positive Allosteric Modulators
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