Abstract
Ferroportin—the only known cellular iron exporter—is responsible for iron efflux from enterocytes and macrophages to the blood plasma. This transporter, under the control of hepcidin, serves as a key point of regulation in human iron homeostasis. The thermodynamic driving force for ferroportin‐mediated iron efflux is not known at present. To test the hypothesis that ferroportin is an iron/calcium antiporter, we expressed human ferroportin in RNA‐injected Xenopus oocytes and examined its activity by using radiotracer assays as described (Mitchell et al, Am J Physiol Cell Physiol 306: C450–C459, 2014). Ferroportin expression stimulated 55Fe efflux in the presence of 2 mM extracellular Ca2+ [mean (SD) rate constant, k = 3.5 (1.8) × 10−3 min−1; P < 0.001] but not in its absence (0 mM Ca2+, 1 mM EGTA) [k = 0.45 (0.60) × 10−3 min−1], the latter no different from control. Mg2+ could not substitute for Ca2+. Whereas extracellular Ca2+ stimulated ferroportin‐mediated 55Fe efflux (with half‐maximal [Ca], K0.5 ∼ 0.6 mM), microinjection of iron did not stimulate the uptake of 100 μM 45Ca2+ in oocytes expressing ferroportin (P = 0.7). We conclude that calcium is a required cofactor—but not a transported substrate—of ferroportin. Our study suggests that ferroportin‐mediated iron efflux may be limited in conditions of hypocalcemia. DK080047, DK082717
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