Publications

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

  Levy M., Elkoshi N., Barber-Zucker S., Hoch E., Zarivach R., Hershfinkel M., Sekler I.

  Manganese (Mn²⁺) is extruded from the cell by the zinc transporter 10 (ZnT10). Loss of ZnT10 expression caused by autosomal mutations in the <i>ZnT10</i> gene leads to hypermanganesemia in multiple organs. Here, combining fluorescent monitoring of cation influx in HEK293-T cells express ... >> More

  Manganese (Mn²⁺) is extruded from the cell by the zinc transporter 10 (ZnT10). Loss of ZnT10 expression caused by autosomal mutations in the <i>ZnT10</i> 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 spectrally distinguish between Mn²⁺ and Ca²⁺ fluxes. We found that (<i>a</i>) application of Mn²⁺-containing Ca²⁺-free solution to ZnT10-expressing cells triggers an influx of Mn²⁺, (<i>b</i>) reintroduction of Ca²⁺ leads to cellular Mn²⁺ extrusion against an inward Mn²⁺ gradient, and (<i>c</i>) 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. << Less

  J. Biol. Chem. 294:5879-5889(2019) [PubMed] [EuropePMC]