Extracellular calcium sensing and signalling

Hofer, Aldebaran M.; Brown, Edward M.

doi:10.1038/nrm1154

Cited by 575 publications

(548 citation statements)

References 123 publications

Supporting

Mentioning

517

Contrasting

Unclassified

Order By: Relevance

“…FHH may be inherited as an autosomal dominant condition, and it is a genetically heterogeneous disorder with three recognized variants, FHH1‐3. FHH1 (OMIM #145980) is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor (GPCR)3 that initiates activation of the G‐protein subunit αq/11 (Gα q/11 ) family, leading to enhancement of phospholipase C (PLC) activity4 and elevation of inositol 1,4,5‐trisphosphate (IP 3 ) with rapid increase in intracellular calcium (Ca 2+ i ) concentrations 5, 6. These signal transduction events allow the parathyroid CaSR to respond to small fluctuations in the prevailing extracellular calcium concentration ([Ca 2+ ] o ) by inducing alterations in PTH secretion through mechanisms that likely involve effects on PTH mRNA stability7 and PTH granule exocytosis from the apical pole of parathyroid cells 8.…”

Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

show abstract

Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

show abstract

“…A number of mutations in the TMD of class C GPCRs which result in either a gain or a loss of function have been reported, either through site-directed mutagenesis (28) or through the analysis of human gene sequences (29)(30)(31)(32). For example, both gain-and loss-of-function mutations identified in the calciumsensing receptor gene are responsible for autosomal dominant hypocalcemia and familial hypocalciuric hypercalcemia, respectively (33). We examined whether similar mutations introduced in the mGlu2 TMD can affect the dynamics of the ECD dimer.…”

Section: Allosteric Control Of the Relative Movement Of The Ecds By Tmentioning

confidence: 99%

Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors

Doumazane

Scholler

Fabre

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

109

147

View full text Add to dashboard Cite

In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation of the effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.M any cell-surface receptors are multimers of proteins composed of several domains (1-3), including extracellular domains (ECDs) involved in endogenous ligand recognition and transmembrane domains (TMDs) responsible for intracellular signal transduction. Analysis of the conformational changes of the ECDs associated with receptor activation is crucial to understand the detailed mechanism involved in receptor activation and for the development of new innovative drugs. However, limited information is available on how the conformational changes in these proteins lead to receptor activation, especially in living cells.The eight glutamate-activated G-protein-coupled receptors (GPCRs), called "metabotropic glutamate receptors" (mGluRs), are key examples of multidomain and multimeric receptors (Fig. 1A). These receptors are strict dimers (4-6), and each subunit is made of a large ECD associated with a seven-helix TMD responsible for G-protein activation and downstream signaling (7). The mGluRs are key elements involved in the regulation of synaptic activity (8), and therefore they represent promising targets in drug development for the treatment of multiple neurologic and psychiatric diseases (9). More generally, the mGluRs are part of the class C GPCR family that contains structurally related receptors such as the receptors for sweet and umami taste, calcium, basic amino acids, and the inhibitory neurotransmitter GABA (10, 11).Crystallographic studies of the isolated dimeric ECDs and mutagenesis analyses have provided a clear view of the structure of the dimeric ECD and of the initial steps of mGluR activation. The ECD is composed of a Venus flytrap (VFT) bilobate domain containing the agonist binding site (12-15) and a cysteine-rich domain (CRD) that connects the VFT to the TMD (16). The VFTs exist in two major states: an open state (o) in absence of ligand and stabilized by antagonists, and a closed state (c) stabilized by agonists and required for receptor activation (12-15). The VFT dimer is in equilibrium between various conformations, depending on whether one or two VFTs are open or cl...

show abstract

“…Moreover, treatment of monocytes with the p38 MAPK inhibitor SB203580 increased ERK1/2 activation, and this phosphorylation was blocked by the MEK inhibitor PD98059, indicating that there is also cross-talk between ERK1/2 and p38 MAPK in monocytes (42). Changes in extracellular calcium are monitored by the ubiquitously expressed extracellular calcium-sensing receptor (CaR) (43,44). Calcium-or agonist-induced activation of this G protein-coupled receptor has been linked to activation of various MAP kinases, including ERK1/2 (45)(46)(47).…”

Section: P38 Mapk Negatively Regulates Mmp-9 In Oral Cancermentioning

confidence: 99%

Calcium-induced Matrix Metalloproteinase 9 Gene Expression Is Differentially Regulated by ERK1/2 and p38 MAPK in Oral Keratinocytes and Oral Squamous Cell Carcinoma

Mukhopadhyay

Munshi

Kambhampati³

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) play an important role in the invasive behavior of a number of cancers including oral squamous cell cancer (OSCC), and increased expression of MMP-9 is correlated with invasive and metastatic OSCC. Because calcium is an important regulator of keratinocyte function, the effect of modulating extracellular calcium on MMP-9 expression in OSCC cell lines was evaluated. Increasing extracellular calcium induced a dose-dependent increase in MMP-9 expression in immortalized normal and premalignant oral keratinocytes, but not in two highly invasive OSCC cell lines. Differential activation of MAPK signaling was also induced by calcium. p38 MAPK activity was downregulated, whereas ERK1/2 activity was enhanced. Pharmacologic inhibition of p38 MAPK activity or expression of a catalytically inactive mutant of the upstream kinase MAPK kinase 3 (MKK3) increased the calcium induced MMP-9 gene expression, demonstrating that p38 MAPK activity negatively regulated this process. Interestingly blocking p38 MAPK activity enhanced ERK1/2 phosphorylation, suggesting reciprocal regulation between the ERK1/2 and p38 MAPK pathways. Together these data support a model wherein calcium-induced MMP-9 expression is differentially regulated by the ERK1/2 and p38 MAPK pathways in oral keratinocytes, and the data suggest that a loss of this regulatory mechanism accompanies malignant transformation of the oral epithelium.Oral squamous cell carcinoma (OSCC) 1 is the most common malignancy of the oral cavity causing more deaths than any other oral disease (1, 2). Although OSCC is characterized by local, regional, and distant spread, the biochemical factors that underlie dissemination are poorly understood (1, 3). OSCC tumors demonstrate a progressive lack of basement membrane staining, more diffuse invasion, and a higher frequency of lymph node metastasis, suggesting that basement membrane loss reflects metastatic potential (4 -7). This is consistent with immunohistochemical and in situ hybridization studies of human OSCC tumors that implicate enzymes belonging to the matrix metalloproteinase (MMP) family, including MMP-9 (92-kDa gelatinase B), in basement membrane proteolysis and tissue invasion. The presence of gelatinolytic activity attributable to activated MMP-9 in OSCC biopsy specimens correlates with immunohistochemical staining of frozen sections and is enhanced in both highly invasive and metastatic cases, suggesting a correlation between MMP-9 activity and metastatic potential (8,9). Additional studies of human tumors have shown that MMP-9 is up-regulated in diffuse invasive OSCC specimens, with predominant localization to the invasive front (4, 10). At the cellular level, modulation of MMP-9 expression via phorbol ester treatment leads to enhanced invasive behavior (8 -10), whereas blocking MMP-9 expression in vivo reduces invasion in an orthotopic murine model of OSCC (11). These data support the hypothesis that MMP-9 is an important determinant of the invasive phenotype in OSCC.Oral keratinocytes express a...

show abstract

Extracellular calcium sensing and signalling

Cited by 575 publications

References 123 publications

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors

Calcium-induced Matrix Metalloproteinase 9 Gene Expression Is Differentially Regulated by ERK1/2 and p38 MAPK in Oral Keratinocytes and Oral Squamous Cell Carcinoma

Contact Info

Product

Resources

About