Neuronal microRNAs safeguard ER Ca2+ homeostasis and attenuate the unfolded protein response upon stress

Maria Paschou, Panagiota Papazafiri, Chrysanthi Charalampous, Michael Zachariadis, Skarlatos G. Dedos, Epaminondas Doxakis

Research output: Contribution to journalArticlepeer-review

4 Citations (SciVal)

Abstract

Ca2+ is a critical mediator of neurotransmitter release, synaptic plasticity, and gene expression, but also excitotoxicity. Ca2+ signaling and homeostasis are coordinated by an intricate network of channels, pumps, and calcium-binding proteins, which must be rapidly regulated at all expression levels. Τhe role of neuronal miRNAs in regulating ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs) was investigated to understand the underlying mechanisms that modulate ER Ca2+ release. RyRs and IP3Rs are critical in mounting and propagating cytosolic Ca2+ signals by functionally linking the ER Ca2+ content, while excessive ER Ca2+ release via these receptors is central to the pathophysiology of a wide range of neurological diseases. Herein, two brain-restricted microRNAs, miR-124-3p and miR-153-3p, were found to bind to RyR1-3 and IP3R3 3′UTRs, and suppress their expression at both the mRNA and protein level. Ca2+ imaging studies revealed that overexpression of these miRNAs reduced ER Ca2+ release upon RyR/IP3R activation, but had no effect on [Ca2+]i under resting conditions. Interestingly, treatments that cause excessive ER Ca2+ release decreased expression of these miRNAs and increased expression of their target ER Ca2+ channels, indicating interdependence of miRNAs, RyRs, and IP3Rs in Ca2+ homeostasis. Furthermore, by maintaining the ER Ca2+ content, miR-124 and miR-153 reduced cytosolic Ca2+ overload and preserved protein-folding capacity by attenuating PERK signaling. Overall, this study shows that miR-124-3p and miR-153-3p fine-tune ER Ca2+ homeostasis and alleviate ER stress responses.

Original languageEnglish
Article number373
JournalCellular and Molecular Life Sciences
Volume79
Issue number7
Early online date21 Jun 2022
DOIs
Publication statusPublished - 31 Jul 2022

Bibliographical note

Funding Information:
This work was supported by grants from the Greek General Secretariat for Research and Technology (GSRT) to ED (MIS380201, 12RUS-11-65), SGD (ARISTEIA II 4475), and PP (ARISTEIA I 1507). The funders had no role in the study design, the collection, data analysis, or the manuscript's preparation.

Keywords

  • Calcium
  • Inositol 1,4,5-triphosphate receptor
  • miR-124
  • miR-153
  • Ryanodine receptor
  • Unfolded protein response

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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