Calcium-sensing receptor signaling - How human disease informs biology.
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ABSTRACT:
SUBMITTER: Gorvin CM
PROVIDER: S-EPMC7611003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is an expertly curated database of literature-derived functional information for the model organism budding yeast, Saccharomyces cerevisiae. SGD constantly strives to synergize new types of experimental data and bioinformatics predictions with existing data, and to organize them into a comprehensive and up-to-date information resource. The primary mission of SGD is to facilitate research into the biology of yeast and to provide this wealth of information to advance, in many ways, research on other organisms, even those as evolutionarily distant as humans. To build such a bridge between biological kingdoms, SGD is curating data regarding yeast-human complementation, in which a human gene can successfully replace the function of a yeast gene, and/or vice versa. These data are manually curated from published literature, made available for download, and incorporated into a variety of analysis tools provided by SGD.
| S-EPMC5753351 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-07-31 | E-GEOD-68726 | biostudies-arrayexpress
Project description:BackgroundNerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.Methodology/principal findingsBy combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Conclusions/significanceOur experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability.
| S-EPMC2797309 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-07-31 | GSE68726 | GEO
Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions. n=3 CON and KO (each sample contain RNA isolated from neonatal epidermis separated from 3 mice)
2015-07-31 | E-GEOD-68724 | biostudies-arrayexpress
Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions. n=3 CON and KO (each sample contain RNA isolated from neonatal epidermis separated from 3 mice)
2015-07-31 | E-GEOD-68723 | biostudies-arrayexpress
Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions. n=3 CON and DKO (each sample contain RNA isolated from neonatal epidermis separated from 3 mice)
2015-07-31 | E-GEOD-68725 | biostudies-arrayexpress
Project description:Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Introduction: Extracellular Ca2+ concentration (Ca2+ o) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca2+ o-sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures. Methods: Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells. Results: We found that the frequency of Ca2+ o-induced Ca2+ i oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor's C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation. Discussion and Conclusion: CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.
| S-EPMC9931745 | biostudies-literature
Project description:Calcium nephrolithiasis may be considered as a complex disease having multiple pathogenetic mechanisms and characterized by various clinical manifestations. Both genetic and environmental factors may increase susceptibility to calcium stones; therefore, it is crucial to characterize the patient phenotype to distinguish homogeneous groups of stone formers. Family and twin studies have shown that the stone transmission pattern is not mendelian, but complex and polygenic. In these studies, heritability of calcium stones was calculated around 50%Calcium-sensing receptor (CaSR) is mostly expressed in the parathyroid glands and in renal tubules. It regulates the PTH secretion according to the serum calcium concentration. In the kidney, it modulates electrolyte and water excretion regulating the function of different tubular segments. In particular, CaSR reduces passive and active calcium reabsorption in distal tubules, increases phosphate reabsorption in proximal tubules and stimulates proton and water excretion in collecting ducts. Therefore, it is a candidate gene for calcium nephrolithiasis.In a case-control study we found an association between the normocitraturic stone formers and two SNPs of CaSR, located near the promoters region (rs7652589 and rs1501899). This result was replicated in patients with primary hyperparathyroidism, comparing patients with or without kidney stones. Bioinformatic analysis suggested that the minor alleles at these polymorphisms were able to modify the binding sites of specific transcription factors and, consequently, CaSR expression.Our studies suggest that CaSR is one of the candidate genes explaining individual predisposition to calcium nephrolithiasis. Stone formation may be favored by an altered CaSR expression in kidney medulla involving the normal balance among calcium, phosphate, protons and water excretion.
| S-EPMC3339356 | biostudies-literature
Project description:By human sensory analyses, we found that various extracellular calcium-sensing receptor (CaSR) agonists enhance sweet, salty, and umami tastes, although they have no taste themselves. These characteristics are known as "kokumi taste" and often appear in traditional Japanese cuisine. Although GSH is a typical kokumi taste substance (taste enhancer), its mode of action is poorly understood. Here, we demonstrate how the kokumi taste is enhanced by the CaSR, a close relative of the class C G-protein-coupled receptors T1R1, T1R2, and T1R3 (sweet and umami receptors). We identified a large number of CaSR agonist gamma-glutamyl peptides, including GSH (gamma-Glu-Cys-Gly) and gamma-Glu-Val-Gly, and showed that these peptides elicit the kokumi taste. Further analyses revealed that some known CaSR agonists such as Ca(2+), protamine, polylysine, L-histidine, and cinacalcet (a calcium-mimetic drug) also elicit the kokumi taste and that the CaSR-specific antagonist, NPS-2143, significantly suppresses the kokumi taste. This is the first report indicating a distinct function of the CaSR in human taste perception.
| S-EPMC2801228 | biostudies-literature