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Caveolins and intracellular calcium regulation in human airway smooth muscle

Departments of ¹Anesthesiology and ²Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 4 April 2007 ; accepted in final form 10 August 2007

Regulation of intracellular Ca²⁺ concentration ([Ca²⁺]_i) is a key factor in airway smooth muscle (ASM) tone. In vascular smooth muscle, specialized membrane microdomains (caveolae) expressing the scaffolding protein caveolin-1 are thought to facilitate cellular signal transduction. In human ASM cells, we tested the hypothesis that caveolae mediate Ca²⁺ responses to agonist stimulation. Fluorescence immunocytochemistry with confocal microscopy, as well as Western blot analysis, was used to determine that agonist receptors (M₃ muscarinic, bradykinin, and histamine) and store-operated Ca²⁺ entry (SOCE)-regulatory mechanisms colocalize with caveolin-1. Although caveolin-2 coexpressed with caveolin-1, caveolin-3 was absent. In fura 2-loaded ASM cells, [Ca²⁺]_i responses to 1 µM ACh, 10 µM histamine, and 10 nM bradykinin, as well as SOCE, were attenuated (each to a different extent) after disruption of caveolae by the cholesterol-chelating drug methyl--cyclodextrin. Transfection of ASM cells with 50 nM caveolin-1 small interfering RNA significantly weakened caveolin-1 expression and blunted [Ca²⁺]_i responses to bradykinin and histamine, as well as SOCE, but the response to ACh was less intense. These results indicate that caveolae are present in ASM and that caveolin-1 contributes to regulation of [Ca²⁺]_i responses to agonist.

intracellular signaling pathway; methyl--cyclodextrin; small interfering RNA; store-operated calcium entry

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