Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics

Mayr, B; Glaudo, Markus; Schöfl, Christof

doi:10.1016/j.tem.2016.05.005

Cited by 14 publications

(11 citation statements)

References 81 publications

(125 reference statements)

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“…Interestingly, calcilytics agnostic to the serum calcium level stimulate the transient pulses of PTH secretion and act in a similar way as the intermittent PTH does . Different calcilytics such as ronacaleret (also known as SB‐751689), NPSP‐795 (also known as SB‐423562), encaleret (also known as MK‐5442) (Figure ),and AXT914 have been tested in clinical trials, however, these are not devoid of certain side effects including hypercalcemia …”

Section: Current Osteoporosis Treatmentmentioning

confidence: 99%

The underlying pathophysiology and therapeutic approaches for osteoporosis

Awasthi

Mani

Singh

et al. 2018

Medicinal Research Reviews

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With an increase in the ageing population worldwide, the prevalence of osteoporosis increases at an alarming rate in both male and female irrespective of their ethnicity. At present, the currently available therapeutic options are mostly limited to either bone resorptive or bone forming efficacies and both approaches are associated with serious side effects. Despite these options, there is still need for newer therapeutics to treat osteoporosis, which can offer beneficial effects for maintaining balanced dynamics between bone formation and bone resorption, devoid of any side effect. The proper understanding of pathophysiology of the disease is essential for designing or investigating an effective and safe anti-osteoporotic agent. This review represents a discussion around the molecular targets with their implications in disease progression, available therapeutic options, the emerging targets, and the importance of designing an effective anti-osteoporotic agent.

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Section: Current Osteoporosis Treatmentmentioning

confidence: 99%

The underlying pathophysiology and therapeutic approaches for osteoporosis

Awasthi

Mani

Singh

et al. 2018

Medicinal Research Reviews

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“…15,49,50 We used two reported mutations, one activating, CaSR-E228K, and one inactivating, CaSR-R185Q, to assess their effects on the WNK4-SPAK-NCC pathway. [51][52][53] We transfected HEK-293 cells with the WT CaSR or the mutants with WNK4 and observed that CaSR-E228K increased WNK4 abundance ( Figure 3, A and C). We reasoned that if CaSR was acting by the same signal transduction pathway as the AT1 receptor, the presence of KLHL3 would enhance this effect on WNK4.…”

Section: An Activating Mutation Of Casr Increases Wnk4 Abundancementioning

confidence: 99%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca excretion and NaCl reabsorption in response to extracellular Ca However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. We used a combination of and models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Thiazide-sensitive Na uptake assays in oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Activation of CaSR can increase NCC activity the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca reabsorption, further promoting hypercalciuria.

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“…40 CaSR antagonists (calcilytics) in development are a promising solution for CASR activating mutations. 41 …”

Section: Monogenic Causes Of Stone Diseasementioning

confidence: 99%

Personalized Intervention in Monogenic Stone Formers

et al. 2018

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Purpose Treatment of a first-time renal stone consists of acute management followed by medical efforts to prevent stone recurrence. Although nephrolithiasis is roughly 50% heritable, the presence of a family history usually does not affect treatment since most stone disease is regarded as polygenic, ie not attributable to a single gene. Recent evidence has suggested that single mutations could be responsible for a larger proportion of renal stones than previously thought. This intriguing possibility holds the potential to change the management paradigm in stone prevention from metabolically directed therapy to more specific approaches informed by genetic screening and testing. This review synthesizes new findings concerning monogenic kidney stone disease, and provides a concise and clinically useful reference for monogenic causes. It is expected that increased awareness of these etiologies will lead to increased use of genetic testing in recurrent stone formers and further research into the prevalence of monogenic stone disease. Materials and Methods We assembled a complete list of genes known to cause or influence nephrolithiasis based on recent reviews and commentaries. We then comprehensively searched PubMed® and Google Scholar™ for all research on each gene having a pertinent role in nephrolithiasis. We determined which genes could be considered monogenic causes of nephrolithiasis. One gene, ALPL, was excluded since nephrolithiasis is a relatively minor aspect of the disorder associated with the gene (hypophosphatasia). We summarized selected studies and assembled clinically relevant details. Results A total of 27 genes were reviewed in terms of recent findings, mode of inheritance of stone disease, known or supposed prevalence of mutations in the general population of stone patients and specific therapies or considerations. Conclusions There is a distinct opportunity for increased use of genetic testing to improve the lives of pediatric and adult stone patients. Several genes first reported in association with rare disease may be loci for novel mutations, heterozygous disease and forme frustes as causes of stones in the broader population. Cases of idiopathic nephrolithiasis should be considered as potentially having a monogenic basis.

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Activating Calcium-Sensing Receptor Mutations: Prospects for Future Treatment with Calcilytics

Cited by 14 publications

References 81 publications

The underlying pathophysiology and therapeutic approaches for osteoporosis

The underlying pathophysiology and therapeutic approaches for osteoporosis

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Personalized Intervention in Monogenic Stone Formers

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