title: Characterization of Zinc Influx Transporters (ZIPs) in Pancreatic β Cells: ROLES IN REGULATING CYTOSOLIC ZINC HOMEOSTASIS AND INSULIN SECRETION.
abstract: Zinc plays an essential role in the regulation of pancreatic β cell function, affecting important processes including insulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx transporters (ZIPs). In this study, we examined the β cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human and mouse islets and MIN6 β cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic β cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this dysregulated cytosolic zinc homeostasis led to impaired insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast two-hybrid assay. Knock-down of ZIP6 but not ZIP7 in MIN6 β cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway. Therefore, our data suggest that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in β cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on β cell survival.
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Battsetseg
authors.initials: B
authors.lastname: Batchuluun
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Louisa
authors.initials: L
authors.lastname: Ho
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Kacey J
authors.initials: KJ
authors.lastname: Prentice
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Alpana
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Pourasgari
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Alexandre B
authors.initials: AB
authors.lastname: Hardy
authors.affiliation: the Breast Cancer Molecular Pharmacology Unit, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VIIth Avenue, Cardiff CF10 3NB United Kingdom.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Taylor
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.
authors.forename: Herbert
authors.initials: H
authors.lastname: Gaisano
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and f.dai@utoronto.ca.
authors.forename: Feihan F
authors.initials: FF
authors.lastname: Dai
authors.affiliation: From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and Michael.wheeler@utoronto.ca.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D017209:Apoptosis; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D009363:Neoplasm Proteins; D018027:Receptors, Glucagon; C418627:SLC39A6 protein, human; C102227:SLC39A7 protein, human; D052216:Glucagon-Like Peptide 1; D015032:Zinc
keywords: GLP1; exocytosis; glucose; insulin granule; insulin secretion; pancreatic islet; zinc; zinc influx transporter