Redox tuning of Ca2+ signaling in microglia drives glutamate release during hypoxia

Publication date: Available online 2 March 2018
Source:Free Radical Biology and Medicine
Author(s): Renato Socodatoa, Camila C. Portugal, Artur Rodrigues, Joana Henriques, Carla Rodrigues, Cláudia Figueira, João B. Relvas
Hypoxia causes oxidative stress and excitotoxicity, culminating in neuronal damage during brain ischemia. Hypoxia also activates microglia, the myeloid resident cells of the brain parenchyma. Upon activation, microglia release high amounts of the neurotransmitter glutamate, contributing for neuronal excitotoxicity during brain insults. Here, we reveal a signaling pathway controlling glutamate release from human microglia during hypoxia. We show that hypoxia-mediated redox imbalance promotes the activation of endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP3) receptors leading to Ca²⁺ mobilization into the cytosol. Increasing cytosolic Ca²⁺ signaling in microglia activates the non-receptor protein tyrosine kinase Src at the plasma membrane. Src activation enhances the permeability of microglial gap junctions promoting the release of glutamate during hypoxia. Preventing the hypoxia-triggered redox imbalance, using the dietary antioxidants neo-chlorogenic acid or vitamin C, inhibits InsP3-depedent Ca²⁺ signaling and abrogates the release of glutamate. Overall, modulating microglial Ca²⁺ signaling in response to changes in the redox microenvironment might be critical for controling glutamate excitotoxicity during hypoxia.

Graphical abstract

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