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This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/L438    most recent 00222.2006v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Hirota, S. Articles by Janssen, L. J. Search for Related Content PubMed PubMed Citation Articles by Hirota, S. Articles by Janssen, L. J.

The reverse mode of the Na⁺/Ca²⁺ exchanger provides a source of Ca²⁺ for store refilling following agonist-induced Ca²⁺ mobilization

Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Submitted 15 June 2006 ; accepted in final form 11 October 2006

Agonist-induced contraction of airway smooth muscle (ASM) can be triggered by an elevation in the intracellular Ca²⁺ concentration, primarily through the release of Ca²⁺ from the sarcoplasmic reticulum (SR). The refilling of the SR is integral for subsequent contractions. It has been suggested that Ca²⁺ entry via store-operated cation (SOC) and receptor-operated cation channels may facilitate refilling of the SR. Indeed, depletion of the SR activates substantial inward SOC currents in ASM that are composed of both Ca²⁺ and Na⁺. Accumulation of Na⁺ within the cell may regulate Ca²⁺ handling in ASM by forcing the Na⁺/Ca²⁺ exchanger (NCX) into the reverse mode, leading to the influx of Ca²⁺ from the extracellular domain. Since depletion of the SR activates substantial inward Na⁺ current, it is conceivable that the reverse mode of the NCX may contribute to the intracellular Ca²⁺ pool from which the SR is refilled. Indeed, successive contractions of bovine ASM, evoked by various agonists (ACh, histamine, 5-HT, caffeine) were significantly reduced upon removal of extracellular Na⁺; whereas contractions evoked by KCl were unchanged by Na⁺ depletion. Ouabain, a selective inhibitor of the Na⁺/K⁺ pump, had no effect on the reductions observed under normal and zero-Na⁺ conditions. KB-R7943, a selective inhibitor of the reverse mode of the NCX, significantly reduced successive contractions induced by all agonists without altering KCl responses. Furthermore, KB-R7943 abolished successive caffeine-induced Ca²⁺ transients in single ASM cells. Together, these data suggest a role for the reverse mode of the NCX in refilling the SR in ASM following Ca²⁺ mobilization.

calcium handling; airway smooth muscle; sodium-calcium exchanger

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