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Am J Physiol Lung Cell Mol Physiol (January 20, 2006). doi:10.1152/ajplung.00393.2005
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Submitted on September 13, 2005
Accepted on January 12, 2006

Intracellular Cl- fluxes play a novel role in Ca2+-handling in airway smooth muscle

Simon Hirota1, Nancy Trimble1, Evi Pertens1, and Luke J Janssen1*

1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada

* To whom correspondence should be addressed. E-mail: janssenl{at}mcmaster.ca.

Intracellular Ca2+ (Ca2+i) is actively sequestered into the sarcoplasmic reticulum (SR), whereas the release of Ca2+ from the SR can be triggered by activation of the inositol-1,4,5-trisphosphate and ryanodine receptors. Uptake and release of Ca2+ across the SR membrane are electrogenic processes; accumulation of positive or negative charge across the SR membrane could electrostatically hinder the movement of Ca2+ into or out of the SR, respectively. We hypothesized that the movement of intracellular Cl- (Cl-i) across the SR membrane neutralizes the accumulation of charge that accompanies uptake and release of Ca2+. Thus inhibition of SR Cl- fluxes will reduce Ca2+ sequestration and agonist-induced release. The Cl- channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB, 10-4 M), previously shown to inhibit SR Cl- channels, significantly reduced the magnitude of successive acetylcholine-induced contractions of airway smooth muscle (ASM), suggesting a run-down of sequestered Ca2+ within the SR. Niflumic acid (10-4 M), a structurally different Cl- channel blocker, had no such effect. Furthermore, NPPB significantly reduced caffeine-induced contraction and increases in intracellular Ca2+ concentration ([Ca2+]i). Depletion of Cl-i accomplished by bathing ASM strips in Cl- free buffer, significantly reduced the magnitude of successive acetylcholine-induced contractions. Additionally, Cl- depletion significantly reduced caffeine-induced increases in [Ca2+]i. Together these data suggest a novel role for Cl-i fluxes in Ca2+-handling in smooth muscle. Since the release of sequestered Ca2+ is the predominate source of Ca2+ for contraction of ASM, targeting Cl-i fluxes may prove useful in the control of ASM hyperresponsiveness associated with asthma.




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