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.
KeywordsChloride channel-7 Osteoclasts Autosomal dominant osteopetrosis type II Bone resorption
We would like to thank Dr. S.V. Reddy for the gift of human osteoclast cDNA library and his valuable comments. We would also like to thank Dr. Andreas Carl and Jeremy Williams for editing the English of this manuscript.
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 17591957 and 19592165) and a Frontier Research Grant.
Conflicts of interest
The authors have no conflict of interest.
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