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Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):10004-9. doi: 10.1073/pnas.1220009110. Epub 2013 May 29.

Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells.

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  • 1Institute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of Bern, 3012 Bern, Switzerland.

Abstract

NHA2 is a sodium/hydrogen exchanger with unknown physiological function. Here we show that NHA2 is present in rodent and human β-cells, as well as β-cell lines. In vivo, two different strains of NHA2-deficient mice displayed a pathological glucose tolerance with impaired insulin secretion but normal peripheral insulin sensitivity. In vitro, islets of NHA2-deficient and heterozygous mice, NHA2-depleted Min6 cells, or islets treated with an NHA2 inhibitor exhibited reduced sulfonylurea- and secretagogue-induced insulin secretion. The secretory deficit could be rescued by overexpression of a wild-type, but not a functionally dead, NHA2 transporter. NHA2 deficiency did not affect insulin synthesis or maturation and had no impact on basal or glucose-induced intracellular Ca(2+) homeostasis in islets. Subcellular fractionation and imaging studies demonstrated that NHA2 resides in transferrin-positive endosomes and synaptic-like microvesicles but not in insulin-containing large dense core vesicles in β-cells. Loss of NHA2 inhibited clathrin-dependent, but not clathrin-independent, endocytosis in Min6 and primary β-cells, suggesting defective endo-exocytosis coupling as the underlying mechanism for the secretory deficit. Collectively, our in vitro and in vivo studies reveal the sodium/proton exchanger NHA2 as a critical player for insulin secretion in the β-cell. In addition, our study sheds light on the biological function of a member of this recently cloned family of transporters.

PMID:
23720317
PMCID:
PMC3683798
DOI:
10.1073/pnas.1220009110
[PubMed - indexed for MEDLINE]
Free PMC Article
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