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

Deisl, Christine; Simonin, Alexandre; Anderegg, Manuel; Albano, Giuseppe; Kovacs, Gergely; Ackermann, Daniel; Moch, Holger; Dolci, Wanda; Thorens, Bernard; Hediger, Matthias; Fuster, Daniel Guido (2013). Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 110(24), pp. 10004-10009. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1220009110

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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.

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