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

Hirota S, Pertens E, Janssen LJ. The reverse mode of the Na /Ca exchanger provides a source of Ca for store refilling following agonist-induced Ca mobilization. Am J Physiol Lung Cell Mol Physiol 292: L438–L447, 2007. First published October 13; doi:10.1152/ajplung.00222.2006.—Agonist-induced contraction of airway smooth muscle (ASM) can be triggered by an elevation in the intracellular Ca concentration, primarily through the release of Ca from the sarcoplasmic reticulum (SR). The refilling of the SR is integral for subsequent contractions. It has been suggested that Ca 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 Ca and Na . Accumulation of Na within the cell may regulate Ca handling in ASM by forcing the Na /Ca exchanger (NCX) into the reverse mode, leading to the influx of Ca 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 Ca 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 Ca 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 Ca mobilization.