Iron induces two distinct Ca²⁺ 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 (Fe²⁺), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe³⁺). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca²⁺]_i) in astrocytes. Administration of Fe²⁺ or Fe³⁺ in μM concentrations evoked [Ca²⁺]_i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca²⁺]_i through two distinct molecular cascades. Uptake of Fe²⁺ by DMT1 inhibits astroglial Na⁺-K⁺-ATPase, which leads to elevation in cytoplasmic Na⁺ concentration, thus reversing Na⁺/Ca²⁺ exchanger and thereby generating Ca²⁺ influx. Uptake of Fe³⁺ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP₃), thus triggering InsP₃ receptor-mediated Ca²⁺ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload.