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Characterization of Zinc Influx Transporters (ZIPs) in pancreatic beta cells: roles in regulating cytosolic zinc homeostasis and insulin secretion

Liu, Ying, Batchuluun, Battsetseg, Ho, Louisa, Zhu, Dan, Prentice, Kacey J., Bhattacharjee, Alpana, Zhang, Ming, Pourasgari, Farzaneh, Hardy, Alexandre B., Taylor, Kathryn Mary, Gaisano, Herbert, Dai, Feihan F. and Wheeler, Michael B. 2015. Characterization of Zinc Influx Transporters (ZIPs) in pancreatic beta cells: roles in regulating cytosolic zinc homeostasis and insulin secretion. Journal of Biological Chemistry 290 , pp. 18757-18769. 10.1074/jbc.M115.640524

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Abstract

Zinc plays an essential role in the regulation of pancreatic beta cell function, affecting important processes including proinsulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in 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 proteins (ZIPs). In the current study, we have examined the beta cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human, mouse islets and MIN6 beta cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic beta cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this deregulated cytosolic zinc homeostasis led to impaired insulin exocytosis and insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast-two-hybrid (MYTH) assay. Knock-down of ZIP6 but not ZIP7 in MIN6 beta cells impaired the protective effects of GLP-1 on fatty acid-induced cell death possibly via reduced p-ERK pathway. Thus, our data suggests that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in beta cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on beta cell survival.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Funders: Wellcome
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 12 May 2015
Last Modified: 04 Jun 2017 08:11
URI: http://orca.cf.ac.uk/id/eprint/73952

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