title: Ryanodine receptor sensitization results in abnormal calcium signaling in airway smooth muscle cells.
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).
authors: 1 School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom.
authors: Huguette
authors: H
authors: Croisier
authors: 2 Lung Inflammation and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Xiahui
authors: X
authors: Tan
authors: 3 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts; and.
authors: Jun
authors: J
authors: Chen
authors: 4 Department of Mathematics, University of Auckland, Auckland, New Zealand.
authors: James
authors: J
authors: Sneyd
authors: 3 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts; and.
authors: Michael J
authors: MJ
authors: Sanderson
authors: 1 School of Mathematical Sciences, University of Nottingham, Nottingham, United Kingdom.
authors: Bindi S
authors: BS
authors: Brook
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D005260:Female; D005786:Gene Expression Regulation; D007114:Immunization; D007155:Immunologic Factors / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000276:immunology / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000276:immunology; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008867:Microtomy; D015233:Models, Statistical; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000276:immunology*; D046509:Tissue Culture Techniques
chemical_list: D007155:Immunologic Factors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
keywords: Ca2+ oscillations; asthma; hypersensitivity; mathematical modeling; precision-cut lung slice