Iron induces two distinct Ca2+ signalling cascades in astrocytes
Wenzheng Guan, Maosheng Xia, Ming Ji, Beina Chen, Shuai Li, Manman Zhang, Shanshan Liang, Binjie Chen, Wenliang Gong, Chengyi Dong, Gehua Wen, Xiaoni Zhan, Dianjun Zhang, Xinyu Li, Yuefei Zhou, Dawei Guan, Alexei Verkhratsky, Baoman Li
Abstract
Abstract 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.