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

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

Submitted 13 September 2005 ; accepted in final form 12 January 2006

Intracellular Ca²⁺ 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) 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, accomplished by bathing ASM strips in Cl^–-free buffer, significantly reduced the magnitude of successive acetylcholine-induced contractions. In addition, Cl^– depletion significantly reduced caffeine-induced increases in [Ca²⁺]_i. Together these data suggest a novel role for Cl fluxes in Ca²⁺ handling in smooth muscle. Because the release of sequestered Ca²⁺ is the predominate source of Ca²⁺ for contraction of ASM, targeting Cl fluxes may prove useful in the control of ASM hyperresponsiveness associated with asthma.

chloride; 5-nitro-2-(3-phenylpropylamino)benzoic acid; niflumic acid; calcium handling; excitation-contraction coupling

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