https://ror.org/04dese585 Centre for Brain Research, Indian Institute of Science, Bangalore, India.
Manipal Academy of Higher Education, Manipal, India.
Life Sci Alliance. 2024 May 15;7(8). doi: 10.26508/lsa.202402594. Print 2024 Aug.
Calcium signaling is integral for neuronal activity and synaptic plasticity. We demonstrate that the calcium response generated by different sources modulates neuronal activity-mediated protein synthesis, another process essential for synaptic plasticity. Stimulation of NMDARs generates a protein synthesis response involving three phases-increased translation inhibition, followed by a decrease in translation inhibition, and increased translation activation. We show that these phases are linked to NMDAR-mediated calcium response. Calcium influx through NMDARs elicits increased translation inhibition, which is necessary for the successive phases. Calcium through L-VGCCs acts as a switch from translation inhibition to the activation phase. NMDAR-mediated translation activation requires the contribution of L-VGCCs, RyRs, and SOCE. Furthermore, we show that IP3-mediated calcium release and SOCE are essential for mGluR-mediated translation up-regulation. Finally, we signify the relevance of our findings in the context of Alzheimer's disease. Using neurons derived from human fAD iPSCs and transgenic AD mice, we demonstrate the dysregulation of NMDAR-mediated calcium and translation response. Our study highlights the complex interplay between calcium signaling and protein synthesis, and its implications in neurodegeneration.
钙信号对于神经元活动和突触可塑性至关重要。我们证明，不同来源产生的钙反应调节神经元活动介导的蛋白质合成，这是突触可塑性所必需的另一个过程。NMDAR 的刺激会产生涉及三个阶段的蛋白质合成反应——增加翻译抑制，然后是翻译抑制的减少，以及翻译激活的增加。我们表明，这些阶段与 NMDAR 介导的钙反应有关。通过 NMDAR 的钙内流引起增加的翻译抑制，这对于后续阶段是必要的。通过 L-VGCC 的钙充当从翻译抑制到激活阶段的开关。NMDAR 介导的翻译激活需要 L-VGCC、RyRs 和 SOCE 的贡献。此外，我们表明，IP3 介导的钙释放和 SOCE 对于 mGluR 介导的翻译上调是必不可少的。最后，我们在阿尔茨海默病的背景下强调了我们发现的相关性。我们使用源自人类 fAD iPSC 和转基因 AD 小鼠的神经元，证明了 NMDAR 介导的钙和翻译反应的失调。我们的研究强调了钙信号和蛋白质合成之间的复杂相互作用，及其在神经退行性变中的意义。
