Back to Search
Start Over
Ryanodine receptor sensitization results in abnormal calcium signaling in airway smooth muscle cells.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2015 Nov; Vol. 53 (5), pp. 703-11. - Publication Year :
- 2015
-
Abstract
- Intracellular Ca(2+) dynamics of airway smooth muscle cells (ASMCs) are believed to play a major role in airway hyperresponsiveness and remodeling in asthma. Prior studies have underscored a prominent role for inositol 1,4,5-triphosphate (IP3) receptors in normal agonist-induced Ca(2+) oscillations, whereas ryanodine receptors (RyRs) appear to remain closed during such Ca(2+) oscillations, which mediate ASMC contraction. Nevertheless, RyRs have been hypothesized to play a role in hyperresponsive Ca(2+) signaling. This could be explained by RyRs being "sensitized" to open more frequently by certain compounds. We investigate the implications of RyR sensitization on Ca(2+) dynamics in ASMC using a combination of mathematical modeling and experiments with mouse precision-cut lung slices. Caffeine is used to increase the sensitivity of RyRs to cytosolic Ca(2+) concentration ([Ca(2+)]i) and sarcoplasmic reticulum Ca(2+) ([Ca(2+)]SR). In ASMCs, high caffeine concentrations (>10 mM) induce a sustained elevation of [Ca(2+)]i. Our mathematical model accounts for this by the activation of store-operated Ca(2+) entry that results from a large increase in the RyR sensitivity to [Ca(2+)]SR and the associated Ca(2+) release, which leads to a reduction of [Ca(2+)]SR. Importantly, our model also predicts that: (1) moderate RyR sensitization induces slow Ca(2+) oscillations, a result experimentally confirmed with low concentrations of caffeine; and (2) high RyR sensitization suppresses fast, agonist-induced Ca(2+) oscillations by inducing substantial store-operated Ca(2+) entry and elevated [Ca(2+)]i. These results suggest that RyR sensitization could play a role in ASMC proliferation (by inducing slow Ca(2+) oscillations) and in airway hyperresponsiveness (by inducing greater mean [Ca(2+)]i for similar levels of contractile agonist).
- Subjects :
- Animals
Calcium immunology
Calcium metabolism
Calcium Signaling
Cell Proliferation drug effects
Computer Simulation
Female
Gene Expression Regulation
Immunization
Inositol 1,4,5-Trisphosphate immunology
Inositol 1,4,5-Trisphosphate metabolism
Inositol 1,4,5-Trisphosphate Receptors genetics
Inositol 1,4,5-Trisphosphate Receptors immunology
Ion Channel Gating drug effects
Kinetics
Lung drug effects
Lung immunology
Lung pathology
Mice
Mice, Inbred BALB C
Microtomy
Models, Statistical
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle pathology
Respiratory Hypersensitivity chemically induced
Respiratory Hypersensitivity genetics
Respiratory Hypersensitivity pathology
Respiratory Mucosa drug effects
Respiratory Mucosa immunology
Respiratory Mucosa pathology
Ryanodine Receptor Calcium Release Channel genetics
Tissue Culture Techniques
Caffeine pharmacology
Immunologic Factors pharmacology
Myocytes, Smooth Muscle immunology
Respiratory Hypersensitivity immunology
Ryanodine Receptor Calcium Release Channel immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4989
- Volume :
- 53
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 25874477
- Full Text :
- https://doi.org/10.1165/rcmb.2014-0386OC