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The human zinc transporter SLC39A2, also known as ZIP2, was shown to mediate zinc transport that could be inhibited at pH &lt;7.0 and stimulated by HCO 3  - , suggesting a Zn 2+ /HCO 3  - cotransport mechanism [Gaither, L. A., and Eide, D. J. (2000) J. Biol. Chem. 275, 5560-5564]. In contrast, recent experiments in our laboratory indicated that the functional activity of ZIP2 increases at acidic pH [Franz, M. C., et al. (2014) J. Biomol. Screening 19, 909-916]. The study presented here was therefore designed to reexamine the findings about the pH dependence and to extend the functional characterization of ZIP2. Our current results show that ZIP2-mediated transport is modulated by extracellular pH but independent of the H + driving force. Also, in our experiments, ZIP2-mediated transport is not modulated by extracellular HCO 3  - . Moreover, a high extracellular [K + ], which induces depolarization, inhibited ZIP2-mediated transport, indicating that the transport mechanism is voltage-dependent. We also show that ZIP2 mediates the uptake of Cd 2+ ( K m ∼ 1.57 μM) in a pH-dependent manner ( K H +  ∼ 66 nM). Cd 2+ transport is inhibited by extracellular [Zn 2+ ] (IC 50 ∼ 0.32 μM), [Cu 2+ ] (IC 50 ∼ 1.81 μM), and to a lesser extent [Co 2+ ], but not by [Mn 2+ ] or [Ba 2+ ]. Fe 2+ is not transported by ZIP2. Accordingly, the substrate selectivity of ZIP2 decreases in the following order: Zn 2+ &gt; Cd 2+ ≥ Cu 2+ &gt; Co 2+ . Altogether, we propose that ZIP2 is a facilitated divalent metal ion transporter that can be modulated by extracellular pH and membrane potential. Given that ZIP2 expression has been reported in acidic environments [Desouki, M. M., et al. (2007) Mol. Cancer 6, 37; Inoue, Y., et al. (2014) J. Biol. Chem. 289, 21451-21462; Tao, Y. T., et al. (2013) Mol. Biol. Rep. 40, 4979-4984], we suggest that the herein described H + -mediated regulatory mechanism might be important for determining the velocity and direction of the transport process.

Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2