Characteristics of ClC7 Cl- channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells
Characteristics of ClC7 Cl- channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells
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DOI：
10.1007/s00424-009-0689-4
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发表时间：
2009-10-01
影响因子：
4.5
通讯作者：
Okabe, Koji
中科院分区：
文献类型：
--
作者：
Kajiya, Hiroshi;Okamoto, Fujio;Okabe, Koji
ClC7氯通道(Clcn7)是破骨细胞性骨吸收的关键基因，在常染色体骨化症II型(ADO II)患者中具有杂合性突变。尽管已知胞外酸化可在转导Clcn7的卵母细胞中诱导ClC7氯电流，但这种酸诱导的氯电流的其他特征以及突变体Clcn7对ADO II的影响仍有待确定。本研究表明，胞外酸化可诱发小鼠破骨细胞的外向氯离子电流。野生型人Clcn7在HEK293细胞中的表达也诱导了酸激活的氯电流的显著增加。这些酸激活的氯电流不受细胞内酸化和[Ca~(2+)](I)升高的影响。具有与G215R的ADO II相关的Clcn7突变的HEK293细胞不显示这些氯电流。这些结果表明，在骨吸收过程中，破骨细胞ClC7Cl-通道在胞外酸化时被激活，而在与ADO II相关的Clcn7突变体中被抑制。
ClC7 Cl- channels (Clcn7) are crucial for osteoclastic bone resorption and have heterozygous mutation in autosomal osteopetrosis type II (ADO II) patients. Although extracellular acidification is known to induce ClC7 Cl- currents in Clcn7-transfected oocytes, other characteristics of this acid-induced Cl- current, as well as the effects of mutant Clcn7 in ADO II, remain to be determined. The present study showed that extracellular acidification evoked outward Cl- currents in mouse osteoclasts. Expression of wild-type human Clcn7 in HEK293 cells also induced a significant increase in acid-activated Cl- currents. These acid-activated Cl- currents were independent of intracellular acidification and [Ca2+](i) increase. HEK293 cells with the Clcn7 mutation associated with ADO II at G215R did not display these Cl- currents. These results suggest that osteoclastic ClC7 Cl- channels are activated under extracellar acidification and suppressed in Clcn7 mutant associated with ADO II during bone resorption.