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A mathematical analysis of agonist- and KCl-induced Ca(2+) oscillations in mouse airway smooth muscle cells.

ABSTRACT: Airway hyperresponsiveness is a major characteristic of asthma and is generally ascribed to excessive airway narrowing associated with the contraction of airway smooth muscle cells (ASMCs). ASMC contraction is initiated by a rise in intracellular calcium concentration ([Ca(2+)](i)), observed as oscillatory Ca(2+) waves that can be induced by either agonist or high extracellular K(+) (KCl). In this work, we present a model of oscillatory Ca(2+) waves based on experimental data that incorporate both the inositol trisphosphate receptor and the ryanodine receptor. We then combined this Ca(2+) model and our modified actin-myosin cross-bridge model to investigate the role and contribution of oscillatory Ca(2+) waves to contractile force generation in mouse ASMCs. The model predicts that: 1), the difference in behavior of agonist- and KCl-induced Ca(2+) waves results principally from the fact that the sarcoplasmic reticulum is depleted during agonist-induced oscillations, but is overfilled during KCl-induced oscillations; 2), regardless of the order in which agonist and KCl are added into the cell, the resulting [Ca(2+)](i) oscillations will always be the short-period, agonist-induced-like oscillations; and 3), both the inositol trisphosphate receptor and the ryanodine receptor densities are higher toward one end of the cell. In addition, our results indicate that oscillatory Ca(2+) waves generate less contraction than whole-cell Ca(2+) oscillations induced by the same agonist concentration. This is due to the spatial inhomogeneity of the receptor distributions.

SUBMITTER: Wang IY

PROVIDER: S-EPMC2849087 | biostudies-other | 2010 Apr

REPOSITORIES: biostudies-other

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A mathematical analysis of agonist- and KCl-induced Ca(2+) oscillations in mouse airway smooth muscle cells.

Wang Inga Y IY Bai Yan Y Sanderson Michael J MJ Sneyd James J

Biophysical journal 20100401 7

Airway hyperresponsiveness is a major characteristic of asthma and is generally ascribed to excessive airway narrowing associated with the contraction of airway smooth muscle cells (ASMCs). ASMC contraction is initiated by a rise in intracellular calcium concentration ([Ca(2+)](i)), observed as oscillatory Ca(2+) waves that can be induced by either agonist or high extracellular K(+) (KCl). In this work, we present a model of oscillatory Ca(2+) waves based on experimental data that incorporate bo ...[more]

PMID: 20371316

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Project description:Increased resistance of airways or blood vessels within the lung is associated with asthma or pulmonary hypertension and results from contraction of smooth muscle cells (SMCs). To study the mechanisms regulating these contractions, we developed a mouse lung slice preparation containing bronchioles and arterioles and used phase-contrast and confocal microscopy to correlate the contractile responses with changes in [Ca(2+)](i) of the SMCs. The airways are the focus of this study. The agonists, 5-hydroxytrypamine (5-HT) and acetylcholine (ACH) induced a concentration-dependent contraction of the airways. High concentrations of KCl induced twitching of the airway SMCs but had little effect on airway size. 5-HT and ACH induced asynchronous oscillations in [Ca(2+)](i) that propagated as Ca(2+) waves within the airway SMCs. The frequency of the Ca(2+) oscillations was dependent on the agonist concentration and correlated with the extent of sustained airway contraction. In the absence of extracellular Ca(2+) or in the presence of Ni(2+), the frequency of the Ca(2+) oscillations declined and the airway relaxed. By contrast, KCl induced low frequency Ca(2+) oscillations that were associated with SMC twitching. Each KCl-induced Ca(2+) oscillation consisted of a large Ca(2+) wave that was preceded by multiple localized Ca(2+) transients. KCl-induced responses were resistant to neurotransmitter blockers but were abolished by Ni(2+) or nifedipine and the absence of extracellular Ca(2+). Caffeine abolished the contractile effects of 5-HT, ACH, and KCl. These results indicate that (a) 5-HT and ACH induce airway SMC contraction by initiating Ca(2+) oscillations, (b) KCl induces Ca(2+) transients and twitching by overloading and releasing Ca(2+) from intracellular stores, (c) a sustained, Ni(2+)-sensitive, influx of Ca(2+) mediates the refilling of stores to maintain Ca(2+) oscillations and, in turn, SMC contraction, and (d) the magnitude of sustained airway SMC contraction is regulated by the frequency of Ca(2+) oscillations.

Dataset Information

A mathematical analysis of agonist- and KCl-induced Ca(2+) oscillations in mouse airway smooth muscle cells.

Publications

A mathematical analysis of agonist- and KCl-induced Ca(2+) oscillations in mouse airway smooth muscle cells.

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