In articular cartilage inflammation, histamine release from mast cells is a key event. It can enhance cytokine production and matrix synthesis and also promote cell proliferation by stimulating chondrocytes. In this study, the functional impact of Ca2+-activated K+ (KCa) channels in the regulation of intracellular Ca2+ concentration ([Ca2+]i) in chondrocytes in response to histamine was examined using OUMS-27 cells, as a model of chondrocytes derived from human chondrosarcoma. Application of histamine induced a significant [Ca2+]i rise and also membrane hyperpolarization, and both effects were mediated by the stimulation of H1 receptors. The histamine-induced membrane hyperpolarization was attenuated to ∼50% by large-conductance KCa (BK) channel blockers, and further reduced by intermediate (IK) and small conductance KCa (SK) channel blockers. The tonic component of histamine-induced [Ca2+]i rise strongly depended on the presence of extracellular Ca2+ ([Ca2+]o) and was markedly reduced by La3+ or Gd3+ but not by nifedipine. It was significantly attenuated by BK channel blockers, and further blocked by the cocktail of BK, IK, and SK channel blockers. The KCa blocker cocktail also significantly reduced the store-operated Ca2+ entry (SOCE), which was induced by Ca2+ addition after store-depletion by thapsigargin in [Ca2+]o free solution. Our results demonstrate that the histamine-induced membrane hyperpolarization in chondrocytes due to KCa channel activation contributes to sustained Ca2+ entry mainly through SOCE channels in OUMS-27 cells. Thus, KCa channels appear to play an important role in the positive feedback mechanism of [Ca2+]i regulation in chondrocytes in the presence of articular cartilage inflammation.
Abstract. The contribution of Cl− conductance relative to that of K + in the regulation of membrane potential was examined using OUMS-27 cells, a model cell-line of human chondrocytes. Application of 100 μM niflumic acid (NFA) and other anion-channel blockers induced significant membrane hyperpolarization. The NFA-sensitive membrane current under voltage-clamp was predominantly Cl − current. Application of NFA induced small but significant increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) and markedly enhanced the late component of [Ca 2+ ] i rise induced by 1 μM histamine. In conclusion, Cl − conductance substantially contributes to the regulation of resting membrane potential and [Ca 2+ ] i in OUMS-27 cells.
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