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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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