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

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.