Extracellular transglutaminase-2, nude or associated with astrocytic extracellular vesicles, modulates neuronal calcium homeostasis

Tonoli, E ORCID: https://orcid.org/0000-0001-9774-1048, Verduci, I, Gabrielli, M, Prada, I, Forcaia, G, Coveney, C ORCID: https://orcid.org/0000-0001-7047-6408, Pia Savoca, M, Boocock, DJ ORCID: https://orcid.org/0000-0002-7333-3549, Sancini, G, Mazzanti, M, Verderio, C and Verderio, EAM ORCID: https://orcid.org/0000-0001-9153-8997, 2022. Extracellular transglutaminase-2, nude or associated with astrocytic extracellular vesicles, modulates neuronal calcium homeostasis. Progress in Neurobiology, 216: 102313. ISSN 0301-0082

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Abstract

We have uncovered a novel role for astrocytes-derived extracellular vesicles (EVs) in controlling intraneuronal Ca2+ 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.

Item Type:	Journal article
Publication Title:	Progress in Neurobiology
Creators:	Tonoli, E., Verduci, I., Gabrielli, M., Prada, I., Forcaia, G., Coveney, C., Pia Savoca, M., Boocock, D.J., Sancini, G., Mazzanti, M., Verderio, C. and Verderio, E.A.M.
Publisher:	Elsevier
Date:	September 2022
Volume:	216
ISSN:	0301-0082
Identifiers:	Number Type 10.1016/j.pneurobio.2022.102313 DOI 1557942 Other
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Ward
Date Added:	28 Jun 2022 11:09
Last Modified:	26 Jun 2023 03:00
URI:	https://irep.ntu.ac.uk/id/eprint/46496

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