title: The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression.
abstract: Zinc trafficking in pancreatic beta cells is tightly regulated by zinc transporting (ZNTs) proteins. The role of different ZNTs in the beta cells is currently being clarified. ZNT8 transports zinc into insulin granules and is critical for a correct insulin crystallization and storage in the granules whereas ZNT3 knockout negatively affects beta cell function and survival. Here, we describe for the first time the sub-cellular localization of ZNT3 by immuno-gold electron microscopy and supplement previous data from knockout experiments with investigations of the effect of ZNT3 in a pancreatic beta cell line, INS-1E overexpressing ZNT3. In INS-1E cells, we found that ZNT3 was abundant in insulin containing granules located close to the plasma membrane. The level of ZNT8 mRNA was significantly decreased upon over-expression of ZNT3 at different glucose concentrations (5, 11 and 21 mM glucose). ZNT3 over-expression decreased insulin content and insulin secretion whereas ZNT3 over-expression improved the cell survival after 24 h at varying glucose concentrations (5, 11 and 21 mM). Our data suggest that ZNT3 and ZNT8 (known to regulate insulin secretion) have opposite effects on insulin synthesis and secretion possibly by a transcriptional co-regulation since mRNA expression of ZNT3 was inversely correlated to ZNT8 and ZNT3 over-expression reduced insulin synthesis and secretion in INS-1E cells. ZNT3 over-expression improved cell survival.
authors: Department of Biomedicine, Aarhus University, Århus, Denmark. kamille@clin.au.dk.|Department of Clinical Medicine, Aarhus University, Palle Juul-Jensen Boulevard 82, 8200, Århus N, Denmark. kamille@clin.au.dk.
authors: Kamille
authors: K
authors: Smidt
authors: Department of Biomedicine, Aarhus University, Århus, Denmark.
authors: Agnete
authors: A
authors: Larsen
authors: Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
authors: Andreas
authors: A
authors: Brønden
authors: Department of Biomedicine, Aarhus University, Århus, Denmark.
authors: Karen S
authors: KS
authors: Sørensen
authors: Department of Biomedicine, Aarhus University, Århus, Denmark.
authors: Julie V
authors: JV
authors: Nielsen
authors: Department of Biomedicine, Aarhus University, Århus, Denmark.
authors: Jeppe
authors: J
authors: Praetorius
authors: Department of Molecular Biology and Genetics, Aarhus University, Århus, Denmark.
authors: Pia M
authors: PM
authors: Martensen
authors: Department of Biomedicine, Aarhus University, Århus, Denmark.|Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.|Department of Clinical Pharmacology, Rigshospitalet, Copenhagen, Denmark.
authors: Jørgen
authors: J
authors: Rungby
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D065840:Protective Factors; D021381:Protein Transport; D051381:Rats; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D007328:Insulin; C102806:SLC30A3 protein, human; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8
keywords: Beta cell survival; Insulin secretion; Localization; SLC30A3; ZNT3; ZNT8