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J Biol Chem. 2015 Mar 6;290(10):6270-80. doi: 10.1074/jbc.M114.602979. Epub 2015 Jan 14.

Anoctamin-6 controls bone mineralization by activating the calcium transporter NCX1.

Author information

1
From the Institut für Physiologie, Universität Regensburg, D-93053 Regensburg and.
2
the Department Entwicklungsbiologie, Fakultät für Biologie, Universität Duisburg-Essen, 45141 Essen, Germany.
3
From the Institut für Physiologie, Universität Regensburg, D-93053 Regensburg and karl.kunzelmann@ur.de.

Abstract

Anoctamin-6 (Ano6, TMEM16F) belongs to a family of putative Ca(2+)-activated Cl(-) channels and operates as membrane phospholipid scramblase. Deletion of Ano6 leads to reduced skeleton size, skeletal deformities, and mineralization defects in mice. However, it remains entirely unclear how a lack of Ano6 leads to a delay in bone mineralization by osteoblasts. The Na(+)/Ca(2+) exchanger NCX1 was found to interact with Ano6 in a two-hybrid split-ubiquitin screen. Using human osteoblasts and osteoblasts from Ano6(-/-) and WT mice, we demonstrate that NCX1 requires Ano6 to efficiently translocate Ca(2+) out of osteoblasts into the calcifying bone matrix. Ca(2+)-activated anion currents are missing in primary osteoblasts isolated from Ano6 null mice. Our findings demonstrate the importance of NCX1 for bone mineralization and explain why deletion of an ion channel leads to the observed mineralization defect: Ano6 Cl(-) currents are probably required to operate as a Cl(-) bypass channel, thereby compensating net Na(+) charge movement by NCX1.

KEYWORDS:

Anoctamin; Bone; Calcium Transport; Cell Biology; Chloride Channel; Chloride Transport

PMID:
25589784
PMCID:
PMC4358264
DOI:
10.1074/jbc.M114.602979
[Indexed for MEDLINE]
Free PMC Article

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