Presynaptic store-operated Ca(2+) entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress.
Presynaptic store-operated Ca(2+) entry drives excitatory spontaneous neurotransmission and augments endoplasmic reticulum stress.
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突触前储存的CA（2+）进入驱动兴奋性的自发神经传递并增强内质网应激。
DOI：
10.1016/j.neuron.2021.02.023
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发表时间：
2021-04-21
期刊：
影响因子：
16.2
通讯作者：
Kavalali ET
中科院分区：
文献类型：
--
作者：
Chanaday NL;Nosyreva E;Shin OH;Zhang H;Aklan I;Atasoy D;Bezprozvanny I;Kavalali ET
钙库操作的钙内流(SOCE)是由基质相互作用分子(STIM)蛋白介导的内质网(ER)钙离子耗竭而激活的。在这里，我们证明了在大鼠和小鼠海马神经元中，急性内质网钙缺乏通过STIM2和突触钙感受器突触聚集素-7(Syt7)依赖的途径增加突触前钙水平和谷氨酸释放。相反，synaptopagmin-1(Syt1)可以抑制SOCE介导的自发释放，而在syt1功能丧失期间，自发释放的增加需要STIM2。我们还证明，慢性内质网应激激活相同的途径，导致Syt7依赖的自发谷氨酸释放的增强。在内质网应激期间，抑制SOCE或Syt7驱动的融合部分恢复了基础神经传递，减少了促凋亡标志物的表达，表明这些过程参与了内质网应激相关损伤的放大。综上所述，我们认为突触前SOCE将内质网应激和增强的自发神经传递联系在一起，这可能反过来促进神经退化。Chanaday等人。揭示兴奋性突触前终末钙库操作的钙离子进入与神经递质释放之间的潜在分子机制。在慢性内质网应激过程中激活这一机制可能会通过增加谷氨酸的释放来加剧和促进神经元的损伤。
Store operated calcium entry (SOCE) is activated by depletion of Ca2+ 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 Ca2+ depletion increases presynaptic Ca2+ levels and glutamate release through a STIM2 and synaptic Ca2+ sensor synaptotagmin-7 (syt7) dependent pathway. 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. Chanaday et al. uncover the underlying molecular mechanism coupling store-operated Ca2+ entry to neurotransmitter release at excitatory presynaptic terminals. Activation of this mechanism during chronic ER stress may exacerbate and help propagate the neuronal damage via increased glutamate release.
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影响因子：
3
作者：
Garcia-Alvarez G;Shetty MS;Lu B;Yap KA;Oh-Hora M;Sajikumar S;Bichler Z;Fivaz M
通讯作者：
Fivaz M
影响因子：
3.7
作者：
Henderson MJ;Baldwin HA;Werley CA;Boccardo S;Whitaker LR;Yan X;Holt GT;Schreiter ER;Looger LL;Cohen AE;Kim DS;Harvey BK
通讯作者：
Harvey BK
影响因子：
3.3
作者：
Garcia-Alvarez G;Lu B;Yap KA;Wong LC;Thevathasan JV;Lim L;Ji F;Tan KW;Mancuso JJ;Tang W;Poon SY;Augustine GJ;Fivaz M
通讯作者：
Fivaz M
影响因子：
64.8
作者：
HOTH, M;PENNER, R
通讯作者：
PENNER, R
影响因子：
5.3
作者：
Carter, AG;Vogt, KE;Regehr, WG
通讯作者：
Regehr, WG