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Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe 2+ ), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe 3+ ). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca 2+ ] i ) in astrocytes. Administration of Fe 2+  or Fe 3+  in μM concentrations evoked [Ca 2+ ] i  in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca 2+ ] i  through two distinct molecular cascades. Uptake of Fe 2+  by DMT1 inhibits astroglial Na + -K + -ATPase, which leads to elevation in cytoplasmic Na +  concentration, thus reversing Na + /Ca 2+  exchanger and thereby generating Ca 2+  influx. Uptake of Fe 3+  by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP 3 ), thus triggering InsP 3  receptor-mediated Ca 2+  release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload.

Iron induces two distinct Ca2+ signalling cascades in astrocytes