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

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.