Interaction of calcium with the human divalent metal-ion transporter-1

摘要

Iron deficiency is the most prevalent micronutrient deficiency worldwide. Whereas dietary calcium is known to reduce the bioavailability of iron, the molecular basis of this interaction is not understood. We tested the hypothesis that divalent metal-ion transporter-1 (DMT1—the principal or only mechanism by which nonheme iron is taken up at the intestinal brush border—is shared also by calcium. We expressed human DMT1 in RNA-injected Xenopus oocytes and examined its activity using radiotracer assays and the voltage clamp. DMT1 did not mediate ⁴⁵Ca²⁺ uptake. Instead, we found that Ca²⁺ blocked the Fe²⁺-evoked currents and inhibited ⁵⁵Fe²⁺ uptake in a noncompetitive manner (Ki ≈ 20 mM). The mechanism of inhibition was independent of voltage and did not involve intracellular Ca²⁺ signaling. The alkaline earth metal ions Ba²⁺, Sr²⁺ and Mg²⁺ also inhibited DMT1-mediated iron-transport activity. We conclude that Ca²⁺ is a low-affinity noncompetitive inhibitor—but not a transported substrate—of DMT1, explaining in part the effect of high dietary calcium on iron bioavailability.