Physiology and pathophysiology of the calcium-sensing receptor in the kidney

Riccardi, Daniela; Brown, Edward M.

doi:10.1152/ajprenal.00608.2009

Cited by 288 publications

(263 citation statements)

References 167 publications

(196 reference statements)

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“…30 The classic CaSR signaling pathway involves its binding to the G proteins-G q/11 , G i , and G 12/13 -that, in turn, stimulate the phospholipase C, producing diacylglycerol and inositol 1,4,5-trisphosphate and increasing intracellular Ca ++ levels. 3 The calcineurin-NFAT pathway, a canonical intracellular Ca ++ signaling mechanism, responds to changes in intracellular Ca ++ by turning on or off a variety of genes in different tissues. 21 In the TALH of the kidney, there have been reports showing a generic increase in calcineurin activity on CaSR activation that seemed to be required for the production of TNF and prostaglandins.…”

Section: Discussionmentioning

confidence: 99%

“…2 In the kidney, CaSR regulates the Ca ++ excretion through changes in the paracellular channel permeability located in the thick ascending limb of Henle's loop (TALH). 3 Nevertheless, how CaSR regulates paracellular transport in the kidney has long been a mystery. Here, with CaSR-specific pharmacologic reagents, we have shown that CaSR regulates the gene expression of claudin-14 in the kidney transiently.…”

Section: ++mentioning

confidence: 99%

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Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Gong

Hou

2014

Journal of the American Society of Nephrology

109

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Pathologic dysregulation of extracellular calcium metabolism is difficult to correct. The extracellular Ca ++ -sensing receptor (CaSR), a G protein-coupled receptor that regulates renal Ca ++ handling through changes in paracellular channel permeability in the thick ascending limb, has emerged as an effective pharmacological candidate for managing calcium metabolism. However, manipulation of CaSR at the systemic level causes promiscuous effects in the parathyroid glands, kidneys, and other tissues, and the mechanisms by which CaSR regulates paracellular transport in the kidney remain unknown. Here, we describe a CaSR-NFATc1-microRNAclaudin-14 signaling pathway in the kidney that underlies paracellular Ca ++ reabsorption through the tight junction. With CaSR-specific pharmacological reagents, we show that the in vivo gene expression of claudin-14 is regulated through a transcriptional mechanism mediated by NFATc1-microRNA and associated chromatin remodeling. Transgenic knockout and overexpression approaches showed that claudin-14 is required for CaSR-regulated renal Ca ++ metabolism. Together, our results define an important signaling cascade that, when dysregulated, may mediate Ca ++ imbalance through changes in tight junction permeability.

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Section: Discussionmentioning

confidence: 99%

Section: ++mentioning

confidence: 99%

Claudin-14 Underlies Ca++-Sensing Receptor–Mediated Ca++ Metabolism via NFAT-microRNA–Based Mechanisms

Gong

Hou

2014

Journal of the American Society of Nephrology

109

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“…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. Moreover, the kidney CaSR is considered to influence urinary calcium excretion by modulating expression of claudin proteins that mediate the paracellular reabsorption of calcium in the renal thick ascending limb 9, 10. FHH2 (OMIM #145981) is the result of loss‐of‐function mutations in the G‐protein subunit‐α11 (Gα 11 ), encoded by GNA11 , and to date only two FHH2‐associated Gα 11 missense mutations have been reported (Fig.…”

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

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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).

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“…14,25,28 In addition, this effect obliterates the voltage-driving force for calcium reabsorption and raises luminal calcium concentrations in the distal nephron. 25 Furthermore, metabolic alkalosis, initiated by alkali ingestion, increases the affinity of CaSR for calcium, thereby enhancing the inhibition of sodium and calcium reabsorption.…”

mentioning

confidence: 99%

“…Increased intracellular pH stimulates the activity of TRPV5, thereby enhancing calcium resorption and potentially worsening hypercalcemia. 14,28 The activation of CaSR by the presence of increased luminal calcium also stimulates TRPV5-mediated 29 In the collecting duct system, luminal activation of CaSR as a result of excess luminal calcium concentration enhances both H ϩ -ATPase pump activity and the downregulation of aquaporin 2 expression, leading to urinary acidification, systemic HCO 3 Ϫ generation, and polyuria. These latter effects have been proposed as a mechanism that normally protects the kidney from calcification induced by hypercalciuria but would tend to foster volume depletion and metabolic alkalosis.…”

mentioning

confidence: 99%