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Calcineurin Controls Expression of EAAT1/GLAST in Mouse and Human Cultured Astrocytes through Dynamic Regulation of Protein Synthesis and Degradation

1
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy
2
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy
3
Amsterdam UMC, University of Amsterdam, Department of (Neuro) Pathology, 1105 AZ Amsterdam, The Netherlands
4
Stichting Epilepsie Instellingen Nederland (SEIN), 2103 Heemstede, The Netherlands
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 2213; https://doi.org/10.3390/ijms21062213
Received: 12 March 2020 / Revised: 19 March 2020 / Accepted: 21 March 2020 / Published: 23 March 2020
(This article belongs to the Section Molecular Neurobiology)
Alterations in the expression of glutamate/aspartate transporter (GLAST) have been associated with several neuropathological conditions including Alzheimer’s disease and epilepsy. However, the mechanisms by which GLAST expression is altered are poorly understood. Here we used a combination of pharmacological and genetic approaches coupled with quantitative PCR and Western blot to investigate the mechanism of the regulation of GLAST expression by a Ca2+/calmodulin-activated phosphatase calcineurin (CaN). We show that treatment of cultured hippocampal mouse and fetal human astrocytes with a CaN inhibitor FK506 resulted in a dynamic modulation of GLAST protein expression, being downregulated after 24–48 h, but upregulated after 7 days of continuous FK506 (200 nM) treatment. Protein synthesis, as assessed by puromycin incorporation in neo-synthesized polypeptides, was inhibited already after 1 h of FK506 treatment, while the use of a proteasome inhibitor MG132 (1 μM) shows that GLAST protein degradation was only suppressed after 7 days of FK506 treatment. In astrocytes with constitutive genetic ablation of CaN both protein synthesis and degradation were significantly inhibited. Taken together, our data suggest that, in cultured astrocytes, CaN controls GLAST expression at a posttranscriptional level through regulation of GLAST protein synthesis and degradation. View Full-Text
Keywords: astrocytes; calcineurin; GLAST; protein synthesis; protein degradation; proteostasis astrocytes; calcineurin; GLAST; protein synthesis; protein degradation; proteostasis
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Dematteis, G.; Restelli, E.; Chiesa, R.; Aronica, E.; Genazzani, A.A.; Lim, D.; Tapella, L. Calcineurin Controls Expression of EAAT1/GLAST in Mouse and Human Cultured Astrocytes through Dynamic Regulation of Protein Synthesis and Degradation. Int. J. Mol. Sci. 2020, 21, 2213.

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