Center for Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), Soranou Efesiou 4, 11527, Athens, Greece.
Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece.
Cell Mol Life Sci. 2022 Jun 21;79(7):373. doi: 10.1007/s00018-022-04398-9.
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.
钙是神经递质释放、突触可塑性和基因表达的关键介质，但也是兴奋毒性的关键介质。钙信号和动态平衡是通过一个复杂的通道、泵和钙结合蛋白网络来协调的，这个网络必须在所有表达水平上迅速调节。研究神经元微小 RNA （miRNA）在调节肌浆网钙释放通道（RyR）和肌醇 1,4,5-三磷酸受体（IPR）中的作用，以了解调节内质网 Ca 释放的潜在机制。RyR 和 IPR 通过功能上连接内质网 Ca 含量，在引发和传播细胞溶质 Ca 信号方面起着至关重要的作用，而通过这些受体过度释放内质网 Ca 是广泛的神经病变理生理学的核心。在此，发现两种大脑特异性微小 RNA ，miR-124-3p 和 miR-153-3p ，与 RyR1-3 和 IPR3 3'UTR 结合，并在 mRNA 和蛋白质水平上抑制其表达。钙成像研究表明，这些 miRNA 的过表达减少了 RyR/IPR 激活时内质网 Ca 的释放，但在静止状态下对[Ca]没有影响。有趣的是，导致内质网 Ca 过度释放的处理降低了这些 miRNA 的表达，并增加了其靶内质网 Ca 通道的表达，表明 miRNA、RyR 和 IPR 之间在 Ca 动态平衡中的相互依赖性。此外，通过维持内质网 Ca 含量，miR-124 和 miR-153 通过减轻 PERK 信号来减少细胞溶质 Ca 过载和维持蛋白质折叠能力。总的来说，这项研究表明，miR-124-3p 和 miR-153-3p 精细调节内质网 Ca 动态平衡并减轻内质网应激反应。
