Imperial College London
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ProfessorAylinHanyaloglu

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Professor in Molecular Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2128a.hanyaloglu Website

 
 
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Assistant

 

Miss Kiran Dosanjh +44 (0)20 7594 2176

 
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Location

 

2009Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Babinsky:2016:10.1074/jbc.M115.696401,
author = {Babinsky, VN and Hannan, FM and Gorvin, CM and Howles, SA and Nesbit, MA and Rust, N and Hanyaloglu, AC and Hu, J and Spiegel, AM and Thakker, RV},
doi = {10.1074/jbc.M115.696401},
journal = {Journal of Biological Chemistry},
pages = {10876--10885},
title = {Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein Alpha-11 mutations causing hypercalcemic and hypocalcemic disorders},
url = {http://dx.doi.org/10.1074/jbc.M115.696401},
volume = {291},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Germline loss- and gain-of-function mutations of G-protein alpha-11 (Gα11), which couples the calcium-sensing receptor (CaSR) to intracellular calcium (Ca2+i) signaling, lead to familial hypocalciuric hypercalcemia type 2 (FHH2) and autosomal dominant hypocalcemia type 2 (ADH2), respectively, whereas somatic Gα11 mutations mediate uveal melanoma development by constitutively upregulating MAPK signaling. Cinacalcet and NPS-2143 are allosteric CaSR activators and inactivators, respectively, that ameliorate signaling disturbances associated with CaSR mutations, but their potential to modulate abnormalities of the downstream Gα11 protein is unknown. This study investigated whether cinacalcet and NPS-2143 may rectify Ca2+i alterations associated with FHH2- and ADH2-causing Gα11 mutations, and evaluated the influence of germline gain-of-function Gα11 mutations on MAPK signaling by measuring ERK phosphorylation, and assessed the effect of NPS-2143 on a uveal melanoma Gα11 mutant. WT and mutant Gα11 proteins causing FHH2, ADH2 or uveal melanoma were transfected in CaSR-expressing HEK293 cells, and Ca2+i and ERK1/2 phosphorylation responses measured by flow-cytometry and Alphascreen immunoassay following exposure to extracellular Ca2+ (Ca2+o) and allosteric modulators. Cinacalcet and NPS-2143 rectified the Ca2+i responses of FHH2- and ADH2-associated Gα11 loss- and gain-of-function mutations, respectively. ADH2-causing Gα11 mutations were demonstrated not to be constitutively activating and induced ERK phosphorylation following Ca2+o stimulation only. The increased ERK phosphorylation associated with ADH2 and uveal melanoma mutants was rectified by NPS-2143. These findings demonstrate that CaSR-targeted compounds can rectify signaling disturbances caused by germline and somatic Gα11 mutations, which respectively lead to calcium disorders and tumorigenesis; and that ADH2-causing Gα11 mutations induce non-consti
AU  - Babinsky,VN
AU  - Hannan,FM
AU  - Gorvin,CM
AU  - Howles,SA
AU  - Nesbit,MA
AU  - Rust,N
AU  - Hanyaloglu,AC
AU  - Hu,J
AU  - Spiegel,AM
AU  - Thakker,RV
DO  - 10.1074/jbc.M115.696401
EP  - 10885
PY  - 2016///
SN  - 1083-351X
SP  - 10876
TI  - Allosteric modulation of the calcium-sensing receptor rectifies signaling abnormalities associated with G-protein Alpha-11 mutations causing hypercalcemic and hypocalcemic disorders
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1074/jbc.M115.696401
UR  - http://hdl.handle.net/10044/1/31325
VL  - 291
ER  -
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