Iron induces two distinct Ca2+ signalling cascades in astrocytes

Wenzheng Guan and Maosheng Xia et al. use a combination of pharmacological, genetic, and calcium imaging approaches to describe two mechanisms of iron-induced astrocytic calcium signaling. Altogether, these results suggest that astrocytes may act as a barrier to excessive iron in the brain, thereby improving our understanding of the role of astrocytes in normal neurodevelopment. 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 mu M 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 (InsP(3)), thus triggering InsP(3) 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.

Automated summary

The study reveals two distinct molecular mechanisms by which iron ions trigger calcium signaling in astrocytes, shedding light on the regulation of intracellular calcium concentration in these cells. These findings contribute to our understanding of the functional role of astrocytes in normal neurodevelopment.