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Differential cytolocation and functional assays of the two major SLC30A8 (ZnT8) isoforms

Research output: Contribution to journalArticle

Sandra Carvalho, Jorge Molina-López, Douglas Parsons, Christopher Corpe, Wolfgang Maret, Christer Hogstrand

Original languageEnglish
Pages (from-to)116-124
JournalJournal of Trace Elements in Medicine and Biology
Volume44
Early online date28 Jun 2017
DOIs
Accepted/In press6 Jun 2017
E-pub ahead of print28 Jun 2017
PublishedDec 2017

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Abstract

The non-synonymous single nucleotide polymorphism (SNP) rs13266634 in human zinc transporter 8, ZnT8 (SLC30A8), leads to a R325 variant, which is associated with an increased risk of developing Type 2 Diabetes (T2D). Although the molecular details remain unknown, the mutation is thought to alter the kinetics of zinc transport into insulin granules in pancreatic β-cells. Nevertheless, analysis of ZnT8 sequences from several animals shows that the amino acid at position 325 is poorly conserved. Apart from this particular SNP, human ZnT8 also has two isoforms (splice variants) that differ in length regarding a 49 amino acid N-terminal extension. When expressed in human embryonic kidney (HEK293) cells, the long isoform was present in the plasma membrane in addition to internal membranes, whereas the short isoform was localized mostly to internal membranes. Our observation that human ZnT8 variants and isoforms expressed in Xenopus laevis oocytes are all localized at the cell surface allowed us to develop a zinc transport assay using the radioactive isotope 65Zn. We found no detectable differences in zinc transport between W and R variants and no statistically significant differences between long and short isoforms of the W325 variant. Our findings of different cytolocation of ZnT8 isoforms could be relevant for β-cell zinc metabolism in health and disease.

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