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

Neuronal Store-Operated Ca(2+) Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca(2+) stores and is critical for Ca(2+)-dependent neuronal processes. SOCE sensors, STIM1 and STIM2, can activate Orai, TRP channels and AMPA receptors, and inhibit voltage-gated channels in the...

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Detalles Bibliográficos
Autores principales: Gruszczynska-Biegala, Joanna, Strucinska, Klaudia, Maciag, Filip, Majewski, Lukasz, Sladowska, Maria, Kuznicki, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017226/
https://www.ncbi.nlm.nih.gov/pubmed/31936514
http://dx.doi.org/10.3390/cells9010160
Descripción
Sumario:Neuronal Store-Operated Ca(2+) Entry (nSOCE) plays an essential role in refilling endoplasmic reticulum Ca(2+) stores and is critical for Ca(2+)-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 Ca(2+) contributing to synaptic plasticity and excitotoxicity, remains unclear. Using Ca(2+) 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 [Ca(2+)](i). Modulating STIM protein level through overexpression or shRNA inhibited or activated NMDA-evoked [Ca(2+)](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 Ca(2+) levels, we propose targeting this mechanism as a novel therapeutic strategy against neuropathological conditions that feature NMDA-induced Ca(2+) overload as a diagnostic criterion.