Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1

Abstract

BackgroundActivation of NMDA receptors can induce iron movement into neurons by the small GTPase Dexras1 via the divalent metal transporter 1 (DMT1). This pathway under pathological conditions such as NMDA excitotoxicity contributes to metal-catalyzed reactive oxygen species (ROS) generation and neuronal cell death, and yet its physiological role is not well understood.ResultsWe found that genetic and pharmacological ablation of this neuronal iron pathway in the mice increased glutamatergic transmission. Voltage sensitive dye imaging of hippocampal slices and whole-cell patch clamping of synaptic currents, indicated that the increase in excitability was due to synaptic modification of NMDA receptor activity via modulation of the PKC/Src/NR2A pathway. Moreover, we identified that lysosomal iron serves as a main source for intracellular iron signaling modulating glutamatergic excitability.ConclusionsOur data indicates that intracellular iron is dynamically regulated in the neurons and robustly modulate synaptic excitability under physiological condition. Since NMDA receptors play a central role in synaptic neurophysiology, plasticity, neuronal homeostasis, neurodevelopment as well as in the neurobiology of many diseases, endogenous iron is therefore likely to have functional relevance to each of these areas.

Iron overload contributes to general anaesthesia-induced neurotoxicity and cognitive deficits

“…At the end, it causes the downregulation of NR1, NR2A, and RASD1. The similar feedback regulation was also observed previously [9]. Therefore, it is possible that modulation of iron level is an effective strategy for prevention from NMDARinduced neurotoxicity.…”

“…Evidence proved that NMDAR upregulation could promote iron overload and iron-induced neurotoxicity by enhancing RASD1-DMT1-mediated iron uptake [8] and iron releasing from the lysosome [9]. In the present study, we provided direct evidence that ketamine or sevoflurane exposure caused an upregulation of NMDAR subunits, which might be a compensatory upregulation of NMDAR subunits [34][35][36].…”

“…This diversity of potential targets increases the probability of both positive and negative non-anaesthetic effects. NMDA neurotoxicity can be mediated through an iron transport signalling cascade, i.e., NMDAR upregulation might promote iron overload by enhancing DMT1 (divalent metal transporter 1)-mediated iron influx [8], stimulating iron releasing from lysosome [9], thus causing iron-induced cell damage. Therefore, we question whether iron is involved in GA-induced neurotoxicity.…”

Iron Overload contributes to General Anesthesia-induced Neurotoxicity and Cognitive Deficits

“…At the end, it causes the downregulation of NR1, NR2A, and RASD1. The similar feedback regulation was also observed previously [9]. Therefore, it is possible that modulation of iron level is an effective strategy for prevention from NMDAR-induced neurotoxicity.…”

“…Evidence proved that NMDAR upregulation could promote iron overload and iron-induced neurotoxicity by enhancing RASD1-DMT1-mediated iron uptake [8]and iron releasing from lysosome [9]. In present study, we provided direct evidence that ketamine or sevoflurane exposure caused an upregulation of NMDAR subunits, which might be a compensatory upregulation of NMDAR subunits [34][35][36].…”