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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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.