title: Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells.
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.
authors.affiliation: Institute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of Bern, 3012 Bern, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Deisl
authors.forename: Alexandre
authors.initials: A
authors.lastname: Simonin
authors.forename: Manuel
authors.initials: M
authors.lastname: Anderegg
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Albano
authors.forename: Gergely
authors.initials: G
authors.lastname: Kovacs
authors.forename: Daniel
authors.initials: D
authors.lastname: Ackermann
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Wanda
authors.initials: W
authors.lastname: Dolci
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.forename: Matthias
authors.initials: M
authors.lastname: A Hediger
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fuster
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D034622:RNA Interference; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology
chemical_list: D007328:Insulin; D017923:Sodium-Hydrogen Exchangers; D013453:Sulfonylurea Compounds; D049452:Green Fluorescent Proteins; D005947:Glucose