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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 24; pp. 10004 - 10009
• Main Authors: Deisl, Christine, Simonin, Alexandre, Anderegg, Manuel, Albano, Giuseppe, Kovacs, Gergely, Ackermann, Daniel, Moch, Holger, Dolci, Wanda, Thorens, Bernard, Hediger, Matthias A., Fuster, Daniel G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-06-2013; National Acad Sciences
• Subjects: Animals; Beta cells; Biological Sciences; Cell Line, Tumor; Cell lines; Endocytosis; Endocytosis - drug effects; Endosomes; Endosomes - metabolism; Exocytosis - drug effects; Female; Genotypes; Glucose - pharmacology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kidney cells; Male; Mice; Mice, Knockout; Microscopy, Confocal; RNA Interference; Small interfering RNA; Sodium-Hydrogen Exchangers - genetics; Sodium-Hydrogen Exchangers - metabolism; Sulfonylurea Compounds - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1220009110

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.