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

Ca is a critical mediator of neurotransmitter release, synaptic plasticity, and gene expression, but also excitotoxicity. Ca 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 (IPRs) was investigated to understand the underlying mechanisms that modulate ER Ca release. RyRs and IPRs are critical in mounting and propagating cytosolic Ca signals by functionally linking the ER Ca content, while excessive ER Ca 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 IPR3 3'UTRs, and suppress their expression at both the mRNA and protein level. Ca imaging studies revealed that overexpression of these miRNAs reduced ER Ca release upon RyR/IPR activation, but had no effect on [Ca] under resting conditions. Interestingly, treatments that cause excessive ER Ca release decreased expression of these miRNAs and increased expression of their target ER Ca channels, indicating interdependence of miRNAs, RyRs, and IPRs in Ca homeostasis. Furthermore, by maintaining the ER Ca content, miR-124 and miR-153 reduced cytosolic Ca 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 Ca homeostasis and alleviate ER stress responses.