Calcium/manganese antiporter SLC30A10
calcium:manganese antiporter activity
Zinc transporter 10 (ZnT10)-dependent extrusion of cellular Mn<sup>2+</sup> is driven by an active Ca<sup>2+</sup>-coupled exchange.
Manganese (Mn<sup>2+</sup>) 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 Ca<sup>2+</sup> inward gradient for active cellular exchange of Mn<sup>2+</sup> In analyzing ZnT10 activity we used the ability of Fura-2 to spectrally distinguish between Mn<sup>2+</sup> and Ca<sup>2+</sup> fluxes. We found that (<i>a</i>) application of Mn<sup>2+</sup>-containing Ca<sup>2+</sup>-free solution to ZnT10-expressing cells triggers an influx of Mn<sup>2+</sup>, (<i>b</i>) reintroduction of Ca<sup>2+</sup> leads to cellular Mn<sup>2+</sup> extrusion against an inward Mn<sup>2+</sup> gradient, and (<i>c</i>) the cellular transport of Mn<sup>2+</sup> by ZnT10 is coupled to a reciprocal movement of Ca<sup>2+</sup> Remarkably, replacing a single asparagine residue in ZnT10 (Asp-43) with threonine (ZnT10 N43T) converted the Mn<sup>2+</sup>/Ca<sup>2+</sup> exchange to an uncoupled channel mode, permeable to both Ca<sup>2+</sup> and Mn<sup>2+</sup> The findings in our study identify the first ion transporter that uses the Ca<sup>2+</sup> 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.