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Open AccessArticle

STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons

1
Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology in Warsaw, 02-109 Warsaw, Poland
2
Molecular Biology Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
PhD student at the Postgraduate School of Molecular Medicine, Warsaw Medical University, 02-091 Warsaw, Poland.
Present address: Laboratory of Mitochondrial Biogenesis, The Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland.
Cells 2020, 9(1), 160; https://doi.org/10.3390/cells9010160
Received: 15 December 2019 / Revised: 5 January 2020 / Accepted: 7 January 2020 / Published: 9 January 2020
(This article belongs to the Special Issue Organellar Calcium Signaling in Physiology and Pathophysiology)
Neuronal Store-Operated Ca2+ Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca2+ stores and is critical for Ca2+-dependent neuronal processes. SOCE sensors, STIM1 and STIM2, can activate Orai, TRP channels and AMPA receptors, and inhibit voltage-gated channels in the plasma membrane. However, the link between STIM, SOCE, and NMDA receptors, another key cellular entry point for Ca2+ contributing to synaptic plasticity and excitotoxicity, remains unclear. Using Ca2+ imaging, we demonstrated that thapsigargin-induced nSOCE was inhibited in rat cortical neurons following NMDAR inhibitors. Blocking nSOCE by its inhibitor SKF96365 enhanced NMDA-driven [Ca2+]i. Modulating STIM protein level through overexpression or shRNA inhibited or activated NMDA-evoked [Ca2+]i, respectively. Using proximity ligation assays, immunofluorescence, and co-immunoprecipitation methods, we discovered that thapsigargin-dependent effects required interactions between STIMs and the NMDAR2 subunits. Since STIMs modulate NMDAR-mediated Ca2+ levels, we propose targeting this mechanism as a novel therapeutic strategy against neuropathological conditions that feature NMDA-induced Ca2+ overload as a diagnostic criterion. View Full-Text
Keywords: STIM proteins; NMDA receptor; neuronal store-operated calcium entry (nSOCE); endoplasmic reticulum (ER); plasma membrane (PM); neurons; organellar Ca2+; Ca2+ homeostasis STIM proteins; NMDA receptor; neuronal store-operated calcium entry (nSOCE); endoplasmic reticulum (ER); plasma membrane (PM); neurons; organellar Ca2+; Ca2+ homeostasis
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MDPI and ACS Style

Gruszczynska-Biegala, J.; Strucinska, K.; Maciag, F.; Majewski, L.; Sladowska, M.; Kuznicki, J. STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons. Cells 2020, 9, 160.

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