Calcium-Sensing Receptor Contributes to Hyperoxia-Induced Enhancement of Calcium Regulation and Remodeling in Human Fetal Airway Smooth Muscle

2019 ◽  
Author(s):  
A.M. Roesler ◽  
C.M. Pabelick ◽  
R. Martin ◽  
P. MacFarlane ◽  
Y.S. Prakash
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Regulation ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Calcium sensing receptor in developing human airway smooth muscle

2019 ◽  
Vol 234 (8) ◽  
pp. 14187-14197 ◽  
Author(s):  
Anne M. Roesler ◽  
Sarah A. Wicher ◽  
Jovanka Ravix ◽  
Rodney D. Britt ◽  
Logan Manlove ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Sensing Receptor ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Calcium Sensing

scholarly journals Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan

2020 ◽  
Vol 318 (3) ◽  
pp. L459-L471 ◽  
Author(s):  
Ahmed Lazrak ◽  
Zhihong Yu ◽  
Stephen Doran ◽  
Ming-Yuan Jian ◽  
Judy Creighton ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Smooth Muscle ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Airway Smooth Muscle ◽  
Channel Blocker ◽  
Airway Smooth Muscle Cells ◽  
Low Molecular Weight ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20–25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization ( Vm Air: 62 ± 3 mV; 3 h post Br2:−45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.

scholarly journals Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

2021 ◽  
Vol 12 ◽  
Author(s):  
Anne M. Roesler ◽  
Jovanka Ravix ◽  
Colleen M. Bartman ◽  
Brijeshkumar S. Patel ◽  
Marta Schiliro ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Disease ◽  
Calcium Sensing Receptor ◽  
Pediatric Airway ◽  
Calcium Sensing ◽  
Airway Diseases ◽  
Resident Cell ◽  
Intracellular Ca ◽  
Fetal Lungs

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.

scholarly journals Effect of MgCl2 and GdCl3 on ORAI1 Expression and Store-Operated Ca2+ Entry in Megakaryocytes

2021 ◽  
Vol 22 (7) ◽  
pp. 3292
Author(s):  
Kuo Zhou ◽  
Xuexue Zhu ◽  
Ke Ma ◽  
Jibin Liu ◽  
Bernd Nürnberg ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Transcription Factor ◽  
Smooth Muscle ◽  
Kidney Disease ◽  
Protein Abundance ◽  
Rt Pcr ◽  
Calcium Sensing Receptor ◽  
Transcript Levels ◽  
Calcium Sensing ◽  
Store Depletion

In chronic kidney disease, hyperphosphatemia upregulates the Ca2+ channel ORAI and its activating Ca2+ sensor STIM in megakaryocytes and platelets. ORAI1 and STIM1 accomplish store-operated Ca2+ entry (SOCE) and play a key role in platelet activation. Signaling linking phosphate to upregulation of ORAI1 and STIM1 includes transcription factor NFAT5 and serum and glucocorticoid-inducible kinase SGK1. In vascular smooth muscle cells, the effect of hyperphosphatemia on ORAI1/STIM1 expression and SOCE is suppressed by Mg2+ and the calcium-sensing receptor (CaSR) agonist Gd3+. The present study explored whether sustained exposure to Mg2+ or Gd3+ interferes with the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. To this end, human megakaryocytic Meg-01 cells were treated with 2 mM ß-glycerophosphate for 24 h in the absence and presence of either 1.5 mM MgCl2 or 50 µM GdCl3. Transcript levels were estimated utilizing q-RT-PCR, protein abundance by Western blotting, cytosolic Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and SOCE from the increase in [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, Mg2+ and Gd3+ upregulated CaSR and blunted or virtually abolished the phosphate-induced upregulation of NFAT5, SGK1, ORAI1,2,3, STIM1,2 and SOCE in megakaryocytes. In conclusion, Mg2+ and the CaSR agonist Gd3+ interfere with phosphate-induced dysregulation of [Ca2+]i in megakaryocytes.

scholarly journals Hydrogen sulfide, oxygen, and calcium regulation in developing human airway smooth muscle

2020 ◽  
Vol 34 (9) ◽  
pp. 12991-13004
Author(s):  
Colleen M. Bartman ◽  
Marta Schiliro ◽  
Martin Helan ◽  
Y. S. Prakash ◽  
David Linden ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Airway Smooth Muscle ◽  
Calcium Regulation ◽  
Human Airway Smooth Muscle ◽  
Human Airway

Mitochondrial Calcium Regulation In Human Airway Smooth Muscle

2011 ◽  
Author(s):  
philippe F. delmotte ◽  
Binxia Yang ◽  
Vanessa Zavaletta ◽  
Michael A. Thompson ◽  
YS Prakash ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Regulation ◽  
Mitochondrial Calcium ◽  
Human Airway Smooth Muscle ◽  
Human Airway

scholarly journals Calcium Sensing Receptor Regulating Smooth Muscle Cells Proliferation Through Initiating Cystathionine-Gamma-Lyase/Hydrogen Sulfide Pathway in Diabetic Rat

2015 ◽  
Vol 35 (4) ◽  
pp. 1582-1598 ◽  
Author(s):  
Xin Zhong ◽  
Yuwen Wang ◽  
Jichao Wu ◽  
Aili Sun ◽  
Fan Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Smooth Muscle Cells ◽  
Cyclin D1 ◽  
Western Blotting ◽  
High Glucose ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Aims: Hydrogen sulfide (H2S) inhibits the proliferation of vascular smooth muscle cells (VSMCs). However, how cystathionine-gamma-lyase (CSE), a major enzyme that produces H2S, is regulated remains unknown. Whether calcium-sensing receptor (CaSR) inhibits the proliferation of VSMCs by regulating the endogenous CSE/H2S pathway in diabetic rat has not been previously investigated. Methods and Results: The morphological and ultrastructure alterations were tested by transmission electron microscopy, changes in the H2S concentration and the relaxation of the mesenteric secondary artery loop of diabetic rats were determined by Multiskan spectrum microplate spectrophotometer and isometric force transducer. Additionally, the expression levels of CaSR, CSE and Cyclin D1 in the mesenteric arteries of rats were examined by western blotting. The intracellular calcium concentration, the expression of p-CaMK II (phospho-calmodulin kinases II), CSE activity, the concentration of endogenous H2S and the proliferation of cultured VSMCs from rat thoracic aortas were measured by using confocal microscope, western blotting, microplate spectrophotometer, MTT and BrdU, respectively. The VSMC layer thickened, the H2S concentration dropped, the relaxation of the mesenteric secondary artery rings weakened, and the expression of CaSR and CSE decreased whereas the expression of Cyclin D1 increased in diabetic rats compared with the control group. The [Ca2+]i of VSMCs increased upon treatment with CaSR agonists (10 µM Calindol and 2.5 mM CaCl2), while it decreased upon administration of calhex231, U73122 and 2-APB. The expression of p-CaMK II and CSE increased upon treatment with CaSR agonists in VSMCs. CSE activity and the endogenous H2S concentration decreased in response to high glucose, while it increased with treatment of CaSR agonists. The proliferation rate increased in response to high glucose, and CaSR agonists or NaHS significantly reversed the proliferation of VSMCs caused by high glucose. Conclusions: Our results demonstrated that CaSR regulated the endogenous CSE/H2S pathway to inhibit the proliferation of VSMCs in both diabetic and high glucose models.

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