TY - JOUR
T1 - Neuronal microRNAs safeguard ER Ca2+ homeostasis and attenuate the unfolded protein response upon stress
AU - Paschou, Maria
AU - Papazafiri, Panagiota
AU - Charalampous, Chrysanthi
AU - Zachariadis, Michael
AU - Dedos, Skarlatos G.
AU - Doxakis, Epaminondas
N1 - 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.
PY - 2022/7/31
Y1 - 2022/7/31
N2 - 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.
AB - 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.
KW - Calcium
KW - Inositol 1,4,5-triphosphate receptor
KW - miR-124
KW - miR-153
KW - Ryanodine receptor
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85132303692&partnerID=8YFLogxK
U2 - 10.1007/s00018-022-04398-9
DO - 10.1007/s00018-022-04398-9
M3 - Article
C2 - 35727337
AN - SCOPUS:85132303692
SN - 1420-682X
VL - 79
JO - Cellular and Molecular Life Sciences (CMLS)
JF - Cellular and Molecular Life Sciences (CMLS)
IS - 7
M1 - 373
ER -