1. Extracellular transglutaminase-2, nude or associated with astrocytic extracellular vesicles, modulates neuronal calcium homeostasis.
- Author
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Tonoli E, Verduci I, Gabrielli M, Prada I, Forcaia G, Coveney C, Savoca MP, Boocock DJ, Sancini G, Mazzanti M, Verderio C, and Verderio EAM
- Subjects
- Adenosine Triphosphatases, Calcium metabolism, Homeostasis, Humans, Neurons metabolism, Protein Glutamine gamma Glutamyltransferase 2, Sodium-Calcium Exchanger metabolism, Astrocytes metabolism, Extracellular Vesicles metabolism
- Abstract
We have uncovered a novel role for astrocytes-derived extracellular vesicles (EVs) in controlling intraneuronal Ca
2+ concentration ([Ca2+ ]i ) and identified transglutaminase-2 (TG2) as a surface-cargo of astrocytes-derived EVs. Incubation of hippocampal neurons with primed astrocyte-derived EVs have led to an increase in [Ca2+ ]i , unlike EVs from TG2-knockout astrocytes. Exposure of neurons or brain slices to extracellular TG2 promoted a [Ca2+ ]i rise, which was reversible upon TG2 removal and was dependent on Ca2+ influx through the plasma membrane. Patch-clamp and calcium imaging recordings revealed TG2-dependent neuronal membrane depolarization and activation of inward currents, due to the Na+ /Ca2+ -exchanger (NCX) operating in the reverse mode and indirect activation of L-type VOCCs, as indicated by VOCCs/NCX pharmacological inhibitors. A subunit of Na+ /K+ -ATPase was selected by comparative proteomics and identified as being functionally inhibited by extracellular TG2, implicating Na+ /K+ -ATPase inhibition in NCX reverse mode-switching leading to Ca2+ influx and higher basal [Ca2+ ]i . These data suggest that reactive astrocytes control intraneuronal [Ca2+ ]i through release of EVs with TG2 as responsible cargo, which could have a significant impact on synaptic activity in brain inflammation., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2022
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