scholarly journals Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

2015 ◽  
Vol 7 (284) ◽  
pp. 284ra60-284ra60 ◽  
Author(s):  
Polina L. Yarova ◽  
Alecia L. Stewart ◽  
Venkatachalem Sathish ◽  
Rodney D. Britt ◽  
Michael A. Thompson ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Airway Hyperresponsiveness ◽  
Eosinophil Cationic Protein ◽  
Adenosine Monophosphate ◽  
Asthma Severity ◽  
Mitogen Activated Protein Kinase ◽  
Calcium Sensing Receptor ◽  
Cationic Protein ◽  
Calcium Sensing

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.

Modulation of airway hyperresponsiveness by thiols in a murine in vivo model of allergic asthma

2003 ◽  
Vol 52 (3) ◽  
pp. 126-131 ◽  
Author(s):  
J. Kloek ◽  
I. Van Ark ◽  
F. De Clerck ◽  
N. Bloksma ◽  
F. P. Nijkamp ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Airway Hyperresponsiveness ◽  
In Vivo Model

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Rui Xiao ◽  
Shengquan Luo ◽  
Ting Zhang ◽  
Yankai Lv ◽  
Tao Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Disulfide Bonds ◽  
Acute Hypoxia ◽  
Extracellular Domain ◽  
Left Ventricular ◽  
Extracellular Calcium ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Activation of the CaSR (extracellular calcium-sensing receptor) has been recognized as a critical mediator of hypoxia-induced pulmonary hypertension. Preventive targeting of the early initiating phase as well as downstream events after CaSR activation remains unexplored. As a representative of the G protein-coupled receptor family, CaSR polymerizes on cell surface upon stimulation. Immunoblotting together with MAL-PEG technique identified a reactive oxygen species-sensitive CaSR polymerization through its extracellular domain in pulmonary artery smooth muscle cells upon exposure to acute hypoxia. Fluorescence resonance energy transfer screening employing blocking peptides determined that cycteine129/131 residues in the extracellular domain of CaSR formed intermolecular disulfide bonds to promote CaSR polymerization. The monitoring of intracellular Ca 2+ signal highlighted the pivotal role of CaSR polymerization in its activation. In contrast, the blockade of disulfide bonds formation using a peptide decreased both CaSR and hypoxia-induced mitogenic factor expression as well as other hypoxic-related genes in vitro and in vivo and attenuated pulmonary hypertension development in rats. The blocking peptide did not affect systemic arterial oxygenation in vivo but inhibited acute hypoxia-induced pulmonary vasoconstriction. Pharmacokinetic analyses revealed a more efficient lung delivery of peptide by inhaled nebulizer compared to intravenous injection. In addition, the blocking peptide did not affect systemic arterial pressure, body weight, left ventricular function, liver, or kidney function or plasma Ca 2+ level. In conclusion, a peptide blocking CaSR polymerization reduces its hypoxia-induced activation and downstream events leading to pulmonary hypertension and represents an attractive inhaled preventive alternative worthy of further development.

scholarly journals In vitroRelease of Eosinophil Proteins in Allergic and Atopic Dermatitis Patients

1994 ◽  
Vol 3 (3) ◽  
pp. 223-227 ◽  
Author(s):  
L. K. Poulsen ◽  
C. M. Reimert ◽  
C. Bindslev-Jensen
Keyword(s):  
Atopic Dermatitis ◽  
Eosinophil Cationic Protein ◽  
Coagulation Cascade ◽  
Clotting Time ◽  
Cationic Protein ◽  
Protein X ◽  
Inhalant Allergy ◽  
Different Levels ◽  
Increased Susceptibility

To investigate whether eosinophils are stimulatedin vivoor have acquired an increased susceptibility to stimuli from the coagulation cascade, the release of eosinophil proteins was compared for three groups of donors with different levels of serum IgE. (1) with atopic dermatitis (s-IgE > 5000 IU/ml,n= 11); (2) with inhalant allergy (200 < s-IgE < 2 000 IU/ml,n= 10); and (3) non-allergic (s- IgE < 100 IU/ml,n= 10). The levels of eosinophil cationic protein and eosinophil protein X (ECP, EPX) were determined in serum (clotting time = 2.0 h) and plasma. Serum and plasma ECP in normal donors demonstrated large intra-personal variations (C.V. 50–80%), but serum-ECP (mean 8.1 ng/ml) was clearly distinguishable from plasma ECP (mean 1.0 ng/ml) by a factor of 8 (range: 5.6–11.6). The ECP released during clotting was markedly increased in the atopic dermatitis group (serum:plasma ratio 13.5,p<0.003) compared with the other groups (6.7 and 5.6). EPX, having a higher plasma level, demonstrated a less pronounced release (serum: plasma ratios 2.0, 1.7 and 1.4), with no statistical difference between donor groups. Considering all donors together the levels of ECP and EPX in plasma and in serum were correlated to the number of eosinophils (coefficients of correlation 0.54-0.58,p<0.002).

PTHrP stimulated by the calcium-sensing receptor requires MAP kinase activation

2003 ◽  
Vol 284 (2) ◽  
pp. E435-E442 ◽  
Author(s):  
R. John MacLeod ◽  
Naibedya Chattopadhyay ◽  
Edward M. Brown
Keyword(s):  
Map Kinase ◽  
Map Kinases ◽  
Kinase Inhibitor ◽  
Hormone Secretion ◽  
P38 Map Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Humoral Hypercalcemia Of Malignancy ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Hek Cells

Increases in extracellular calcium concentration ([Ca2+]o) stimulate from normal and malignant cells secretion of parathroid hormone-related protein (PTHrP), a major mediator of humoral hypercalcemia of malignancy. Because the calcium-sensing receptor (CaR) is a determinant of calcium-regulated hormone secretion, we examined whether HEK cells stably transfected with human CaR secreted PTHrP in response to CaR stimulation. Increases in [Ca2+]o or neomycin and Gd3+ all substantially increased PTHrP secretion in CaR-HEK cells but had no effect on nontransfected cells. CaR activation likewise increased PTHrP transcripts. PD-098059 and U-0126, inhibitors of the mitogen-activated protein kinase kinase MEK1/2, abolished CaR-stimulated secretion but had no effect on basal secretion. An inhibitor of p38 MAP kinase, SB-203580, also attenuated CaR-stimulated secretion. Western analysis revealed that CaR activation caused a robust increase in MEK1/2 and p38 MAP kinase phosphorylation. A Src family kinase inhibitor, PP2, blocked both basal and CaR-stimulated secretion. We conclude that CaR specifically mediates the effect of increasing [Ca2+]o on PTHrP synthesis and secretion and that activated MEK1/2 and p38 MAP kinases are determinants of the CaR's stimulation of PTHrP secretion.

scholarly journals The Corpuscles of Stannius, Calcium-Sensing Receptor, and Stanniocalcin: Responses to Calcimimetics and Physiological Challenges

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3002-3010 ◽  
Author(s):  
Michael P. Greenwood ◽  
Gert Flik ◽  
Graham F. Wagner ◽  
Richard J. Balment
Keyword(s):  
Mrna Expression ◽  
Broad Band ◽  
Plasma Concentrations ◽  
Immunoblot Analysis ◽  
Pcr Analysis ◽  
Endocrine Regulation ◽  
Calcium Sensing Receptor ◽  
Corpuscles Of Stannius ◽  
Calcium Sensing

This study has examined whether the calcium-sensing receptor (CaSR) plays a role in control of stanniocalcin-1 (STC-1), the dominant calcium regulatory hormone of fish, comparable with that demonstrated for CaSR in the mediation of ionized calcium regulation of PTH secretion in mammals. In a previous study, we have cloned flounder STC-1 from the corpuscles of Stannius (CS). Here, we report the cloning and characterization of the CS CaSR, and the in vivo responses of this system to altered salinity, EGTA induced hypocalcemia, and calcimimetic administration. Quantitative PCR analysis demonstrated, for the first time, that the CS are major sites of CaSR expression in flounder. Immunoblot analysis of CS proteins with CaSR-specific antibodies revealed a broad band of approximately 215–300 kDa under nonreducing conditions, and bands of approximately 215–300 kDa and approximately 120–150 kDa under reducing conditions. There were no differences in CS CaSR mRNA expression or plasma STC-1 levels between seawater and freshwater (FW)-adapted fish, although CS STC-1 mRNA expression was lower in FW animals. Immunoblots showed that glycosylated monomeric forms of the CaSR migrated at a lower molecular mass in CS samples from FW animals. The ip administration of EGTA rapidly induced hypocalcemia, and a concomitant lowering of plasma STC-1. Calcimimetic administration (1 mg/kg R-568) rapidly increased plasma STC-1 levels, and reduced plasma concentrations of calcium, phosphate, and magnesium when compared with S-568-treated controls. Together, these findings support an evolutionary conserved role for the CaSR in the endocrine regulation of calcium before the appearance of parathyroid glands in tetrapods.

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