Accelerated Ca2+ entry by membrane hyperpolarization due to Ca2+-activated K+ channel activation in response to histamine in chondrocytes.
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 Ca(2+)-activated K(+) (K(Ca)) channels in the regulation of intracellular Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](i) rise and also membrane hyperpolarization, and both effects were mediated by the stimulation of H(1) receptors. The histamine-induced membrane hyperpolarization was attenuated to approximately 50% by large-conductance K(Ca) (BK) channel blockers, and further reduced by intermediate (IK) and small conductance K(Ca) (SK) channel blockers. The tonic component of histamine-induced [Ca(2+)](i) rise strongly depended on the presence of extracellular Ca(2+) ([Ca(2+)](o)) and was markedly reduced by La(3+) or Gd(3+) 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 K(Ca) blocker cocktail also significantly reduced the store-operated Ca(2+) entry (SOCE), which was induced by Ca(2+) addition after store-depletion by thapsigargin in [Ca(2+)](o) free solution. Our results demonstrate that the histamine-induced membrane hyperpolarization in chondrocytes due to K(Ca) channel activation contributes to sustained Ca(2+) entry mainly through SOCE channels in OUMS-27 cells. Thus, K(Ca) channels appear to play an important role in the positive feedback mechanism of [Ca(2+)](i) regulation in chondrocytes in the presence of articular cartilage inflammation.
Funabashi
Kenji
K
Dept. of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City Univ., 3-1 Tanabedori, Mizuhoku, Nagoya 467-8603, Japan.
Ohya
Susumu
S
Yamamura
Hisao
H
Hatano
Noriyuki
N
Muraki
Katsuhiko
K
Giles
Wayne
W
Imaizumi
Yuji
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004155:Diphenhydramine / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D017442:Histamine Agonists / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D011899:Ranitidine / Q000494:pharmacology
D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D006632:Histamine; D011899:Ranitidine; D004155:Diphenhydramine; D002118:Calcium