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.