PT  - JOURNAL ARTICLE
AU  - Eitan Hoch
AU  - Israel Sekler
TI  - Elucidating the H&lt;sup&gt;+&lt;/sup&gt; coupled Zn&lt;sup&gt;2+&lt;/sup&gt; transport mechanism of ZIP4; implications in &lt;em&gt;Acrodermatitis Enteropathica&lt;/em&gt;
AID  - 10.1101/474528
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 474528
4099  - http://biorxiv.org/content/early/2018/11/20/474528.short
4100  - http://biorxiv.org/content/early/2018/11/20/474528.full
AB  - Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely ZnTs (SLC30) that shuttle Zn2+ efflux, and ZIPs (SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3− or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3− failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis Enteropathica, a rare condition of Zn2+ deficiency.