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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/L347    most recent 90559.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bai, Y. Articles by Sanderson, M. J. PubMed PubMed Citation Articles by Bai, Y. Articles by Sanderson, M. J.

The contribution of inositol 1,4,5-trisphosphate and ryanodine receptors to agonist-induced Ca²⁺ signaling of airway smooth muscle cells

Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 10 November 2008 ; accepted in final form 14 May 2009

The relative contribution of inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) and ryanodine receptors (RyRs) to agonist-induced Ca²⁺ signaling in mouse airway smooth muscle cells (SMCs) was investigated in lung slices with phase-contrast or laser scanning microscopy. At room temperature (RT), methacholine (MCh) or 5-hydroxytryptamine (5-HT) induced Ca²⁺ oscillations and an associated contraction in small airway SMCs. The subsequent exposure to an IP₃R antagonist, 2-aminoethoxydiphenyl borate (2-APB), inhibited the Ca²⁺ oscillations and induced airway relaxation in a concentration-dependent manner. 2-APB also inhibited Ca²⁺ waves generated by the photolytic release of IP₃. However, the RyR antagonist ryanodine had no significant effect, at any concentration, on airway contraction or agonist- or IP₃-induced Ca²⁺ oscillations or Ca²⁺ wave propagation. By contrast, a second RyR antagonist, tetracaine, relaxed agonist-contracted airways and inhibited agonist-induced Ca²⁺ oscillations in a concentration-dependent manner. However, tetracaine did not affect IP₃-induced Ca²⁺ release or wave propagation nor the Ca²⁺ content of SMC Ca²⁺ stores as evaluated by Ca²⁺-release induced by caffeine. Conversely, both ryanodine and tetracaine completely blocked agonist-independent slow Ca²⁺ oscillations induced by KCl. The inhibitory effects of 2-APB and absence of an effect of ryanodine on MCh-induced airway contraction or Ca²⁺ oscillations of SMCs were also observed at 37°C. In Ca²⁺-permeable SMCs, tetracaine inhibited agonist-induced contraction without affecting intracellular Ca²⁺ levels indicating that relaxation also resulted from a reduction in Ca²⁺ sensitivity. These results indicate that agonist-induced Ca²⁺ oscillations in mouse small airway SMCs are primary mediated via IP₃Rs and that tetracaine induces relaxation by both decreasing Ca²⁺ sensitivity and inhibiting agonist-induced Ca²⁺ oscillations via an IP₃-dependent mechanism.

lung slices; Ca²⁺-induced Ca²⁺ release; membrane depolarization; tetracaine