Iron induces two distinct Ca 2+ signalling cascades in astrocytes

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.