scholarly journals Positive and Negative Allosteric Modulators Promote Biased Signaling at the Calcium-Sensing Receptor

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1232-1241 ◽  
Author(s):  
Anna E. Davey ◽  
Katie Leach ◽  
Celine Valant ◽  
Arthur D. Conigrave ◽  
Patrick M. Sexton ◽  
...  

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary hyperparathyroidism but is not widely used in earlier stages of renal disease due to the potential to predispose such patients to hypocalcaemia and hyperphosphatemia. The development of a biased CaSR ligand that is more selective for specific signaling pathway(s) leading only to beneficial effects may overcome this limitation. The detection of such stimulus-bias at a G protein-coupled receptor requires investigation across multiple signaling pathways and the development of methods to quantify the effects of allosteric ligands on orthosteric ligand affinity and cooperativity at each pathway. In the current study, we determined the effects of the calcimimetics, NPS-R568 or cinacalcet, and the calcilytic, NPS-2143, on Cao2+-mediated intracellular Ca2+ mobilization, ERK1/2 phosphorylation, and plasma membrane ruffling in a stably transfected human embryonic kidney 293-TREx c-myc-CaSR cell line and applied a novel analytical model to quantify these modulator effects. We present quantitative evidence for the generation of stimulus bias by both positive and negative allosteric modulators of the CaSR, manifested as greater allosteric modulation of intracellular Ca2+ mobilization relative to ERK1/2 phosphorylation, and a higher affinity of the modulators for the state of the CaSR mediating plasma membrane ruffling relative to the other two pathways. Our findings provide the first evidence that an allosteric modulator used in clinical practice exhibits stimulus bias.

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2535 ◽  
Author(s):  
Matilde Colella ◽  
Andrea Gerbino ◽  
Aldebaran M. Hofer ◽  
Silvana Curci

The extracellular calcium-sensing receptor (CaR), a ubiquitous class C G-protein-coupled receptor (GPCR), is responsible for the control of calcium homeostasis in body fluids. It integrates information about external Ca2+ and a surfeit of other endogenous ligands into multiple intracellular signals, but how is this achieved? This review will focus on some of the exciting concepts in CaR signaling and pharmacology that have emerged in the last few years.


GPCRs ◽  
2020 ◽  
pp. 271-282
Author(s):  
Francis S. Willard ◽  
David B. Wainscott

Science ◽  
2007 ◽  
Vol 318 (5852) ◽  
pp. 914c-914c ◽  
Author(s):  
C. A. Johnston ◽  
B. R. Temple ◽  
J.-G. Chen ◽  
Y. Gao ◽  
E. N. Moriyama ◽  
...  

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