Direct Determination of Multiple Ligand Interactions with the Extracellular Domain of the Calcium-sensing Receptor

Zhang, Chen; Zhuo, You; Moniz, Heather; Wang, Shuo; Moremen, Kelley W.; Prestegard, James H.; Brown, Edward M.; Yang, Jenny J.

doi:10.1074/jbc.m114.604652

Cited by 23 publications

(26 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structural requirements for processes such as bias and allosteric modulation of the CaR have been analyzed by recent works [ 95 ]. In addition, a number of papers have highlighted the importance of the potential Ca 2+ binding sites and their relevance for associated diseases [ 8 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]. Recently, the first high-resolution crystal structure of the ECD of the human CaR bound with Mg 2+ has been proposed [ 102 ].…”

Section: The Extracellular Calcium-sensing Receptor (Car)mentioning

confidence: 99%

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

Gerbino

Colella

2018

IJMS

View full text Add to dashboard Cite

The current interest of the scientific community for research in the field of calcium sensing in general and on the calcium-sensing Receptor (CaR) in particular is demonstrated by the still increasing number of papers published on this topic. The extracellular calcium-sensing receptor is the best-known G-protein-coupled receptor (GPCR) able to sense external Ca2+ changes. Widely recognized as a fundamental player in systemic Ca2+ homeostasis, the CaR is ubiquitously expressed in the human body where it activates multiple signalling pathways. In this review, old and new notions regarding the mechanisms by which extracellular Ca2+ microdomains are created and the tools available to measure them are analyzed. After a survey of the main signalling pathways triggered by the CaR, a special attention is reserved for the emerging concepts regarding CaR function in the heart, CaR trafficking and pharmacology. Finally, an overview on other Ca2+ sensors is provided.

show abstract

Section: The Extracellular Calcium-sensing Receptor (Car)mentioning

confidence: 99%

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

Gerbino

Colella

2018

IJMS

View full text Add to dashboard Cite

show abstract

“…The complex glycosylated and high mannose CaSR ECD (residues 20–612) were purified from HEK293S and its mutant cell line (Zhang et al, 2014c ). Using various spectroscopic methods, it was shown that both form the ECD bound to Ca 2+ with a K d of 3.0–5.0 mM.…”

Section: Identification Of Ca 2+ Binding Sites In mentioning

confidence: 99%

“…The hetero-communication between Ca 2+ and an amino acid functions as a dual switch that globally enhances functional positive homotropic cooperative activation of CaSR in response to Ca 2+ signaling by positively impacting multiple Ca 2+ -binding sites within the ECD (Figure 3 ; Zhang et al, 2014a ). A direct interaction between the CaSR ECD and L-Phe was finally reported using saturation transfer difference NMR approaches with a determined binding affinity of ~10 mM in the absence of Ca 2+ (Zhang et al, 2014c ). The study further demonstrated that L-Phe increases the binding affinity of the CaSR ECD for Ca 2+ .…”

Section: Identification Of Amino Acid Binding Site and Heterotropic Fmentioning

confidence: 99%

Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor

et al. 2016

Self Cite

View full text Add to dashboard Cite

Ca2+-sensing receptors (CaSRs) play a central role in regulating extracellular calcium concentration ([Ca2+]o) homeostasis and many (patho)physiological processes in multiple organs. This regulation is orchestrated by a cooperative response to extracellular stimuli such as small changes in Ca2+, Mg2+, amino acids, and other ligands. In addition, CaSR is a pleiotropic receptor regulating several intracellular signaling pathways, including calcium mobilization and intracellular calcium oscillation. Nearly 200 mutations and polymorphisms have been found in CaSR in relation to a variety of human disorders associated with abnormal Ca2+ homeostasis. In this review, we summarize efforts directed at identifying binding sites for calcium and amino acids. Both homotropic cooperativity among multiple calcium binding sites and heterotropic cooperativity between calcium and amino acid were revealed using computational modeling, predictions, and site-directed mutagenesis coupled with functional assays. The hinge region of the bilobed Venus flytrap (VFT) domain of CaSR plays a pivotal role in coordinating multiple extracellular stimuli, leading to cooperative responses from the receptor. We further highlight the extensive number of disease-associated mutations that have also been shown to affect CaSR's cooperative action via several types of mechanisms. These results provide insights into the molecular bases of the structure and functional cooperativity of this receptor and other members of family C of the G protein-coupled receptors (cGPCRs) in health and disease states, and may assist in the prospective development of novel receptor-based therapeutics.

show abstract

“…The ECD contains two sites constantly bound with Ca 2+ and multiple other Ca 2+ -binding sites whose occupancy is dependent on extracellular calcium levels. These varying ECD calcium binding states direct the interaction of the ICD domain with intracellular Ca 2+ [12][13][14].…”

Section: Casr Is Responsible For Cellular Calcium Influxmentioning

confidence: 99%

Calcium and CaSR/IP3R in prostate cancer development

Wang

et al. 2018

Cell Biosci

View full text Add to dashboard Cite

Prostate cancer (PrCa) progression and mortality are associated with calcium metabolism, parathyroid hormone level, and vitamin D level. However, the lack of comprehensive understanding on the molecular rationale of calcium intake, serum homeostasis, and cytoplasmic function, is critically hindering our ability to propose a mechanism based technique for targeting calcium in PrCa. Recently, studies performed on PrCa samples have shown that calcium-sensing receptor regulates cytoplasmic calcium levels in relation to extracellular calcium concentrations. Recent publications have also revealed the role of BAP1 and FBXL2 associated endoplasmic reticular IP3Rs in controlling the trafficking of calcium from cytosol into the mitochondria of PrCa cells. Competitive binding between BAP1, PTEN and FBXL2 to IP3Rs regulates the calcium flux of mitochondria and thereby controls apoptosis. Analysis of data released by Prostate Adenocarcinoma (Provisional TCGA) reveals that calcium related proteins play critical role in the development of PrCa. From this constantly expanding appreciation for the role of calcium outside the muscle, we predict that calciuminduced-calcium-release ryanodine receptors could also be involved in determining cell fate.

show abstract

Direct Determination of Multiple Ligand Interactions with the Extracellular Domain of the Calcium-sensing Receptor

Cited by 23 publications

References 56 publications

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology

Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor

Calcium and CaSR/IP3R in prostate cancer development

Contact Info

Product

Resources

About