Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn2 is driven by an active Ca2-coupled exchange

Moshe Levy, Nadav Elkoshi, Shiran Barber-Zucker, Eitan Hoch, Raz Zarivach, Michal Hershfinkel, Israel Sekler

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Manganese (Mn2) is extruded from the cell by the zinc transporter 10 (ZnT10). Loss of ZnT10 expression caused by auto-somal mutations in the ZnT10 gene leads to hypermanganesemia in multiple organs. Here, combining fluorescent monitoring of cation influx in HEK293-T cells expressing human ZnT10 with molecular modeling of ZnT10 cation selectivity, we show that ZnT10 is exploiting the transmembrane Ca2 inward gradient for active cellular exchange of Mn2. In analyzing ZnT10 activity we used the ability of Fura-2 to spec-trally distinguish between Mn2 and Ca2 fluxes. We found that (a) application of Mn2-containing Ca2-free solution to ZnT10-expressing cells triggers an influx of Mn2, (b) reintroduction of Ca2 leads to cellular Mn2 extrusion against an inward Mn2 gradient, and (c) the cellular transport of Mn2 by ZnT10 is coupled to a reciprocal movement of Ca2. Remarkably, replacing a single asparagine residue in ZnT10 (Asp-43) with threonine (ZnT10 N43T) converted the Mn2/Ca2 exchange to an uncoupled channel mode, permeable to both Ca2 and Mn2. The findings in our study identify the first ion transporter that uses the Ca2 gradient for active counter-ion exchange. They highlight a remarkable versatility in metal selectivity and mode of transport controlled by the tetrahedral metal transport site of ZnT proteins.

Original languageEnglish
Pages (from-to)5879-5889
Number of pages11
JournalJournal of Biological Chemistry
Volume294
Issue number15
DOIs
StatePublished - 12 Apr 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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