Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, TN 37240-7933, USA.
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Neuron. 2021 Apr 21;109(8):1314-1332.e5. doi: 10.1016/j.neuron.2021.02.023. Epub 2021 Mar 11.
Store-operated calcium entry (SOCE) is activated by depletion of Ca from the endoplasmic reticulum (ER) and mediated by stromal interaction molecule (STIM) proteins. Here, we show that in rat and mouse hippocampal neurons, acute ER Ca depletion increases presynaptic Ca levels and glutamate release through a pathway dependent on STIM2 and the synaptic Ca sensor synaptotagmin-7 (syt7). In contrast, synaptotagmin-1 (syt1) can suppress SOCE-mediated spontaneous release, and STIM2 is required for the increase in spontaneous release seen during syt1 loss of function. We also demonstrate that chronic ER stress activates the same pathway leading to syt7-dependent potentiation of spontaneous glutamate release. During ER stress, inhibition of SOCE or syt7-driven fusion partially restored basal neurotransmission and decreased expression of pro-apoptotic markers, indicating that these processes participate in the amplification of ER-stress-related damage. Taken together, we propose that presynaptic SOCE links ER stress and augmented spontaneous neurotransmission, which may, in turn, facilitate neurodegeneration.
钙库操纵性钙内流（SOCE）通过内质网（ER）中钙的耗竭激活，并由基质相互作用分子（STIM）蛋白介导。在这里，我们发现，在大鼠和小鼠海马神经元中，急性 ER 钙耗竭通过依赖于 STIM2 和突触钙传感器突触结合蛋白 7（syt7）的途径增加突触前钙水平和谷氨酸释放。相比之下，突触结合蛋白 1（syt1）可以抑制 SOCE 介导的自发释放，而 STIM2 是在 syt1 功能丧失期间观察到的自发释放增加所必需的。我们还证明，慢性 ER 应激激活相同的途径，导致 syt7 依赖性自发谷氨酸释放增强。在 ER 应激期间，SOCE 或 syt7 驱动融合的抑制部分恢复了基础神经传递，并降低了促凋亡标志物的表达，表明这些过程参与了 ER 应激相关损伤的放大。总之，我们提出，突触前 SOCE 将 ER 应激和增强的自发神经传递联系起来，这可能反过来促进神经退行性变。
