STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs.
STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs.
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DOI：
10.1091/mbc.e14-07-1222
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发表时间：
2015-03-15
影响因子：
3.3
通讯作者：
Fivaz M
中科院分区：
文献类型：
--
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
STIMs(哺乳动物中的STIM1和STIM2)是驻留在内质网中的跨膜蛋白，调节由存储操作的钙离子进入。STIM2介导兴奋性神经元中依赖cAMP/PKA的AMPA受体亚单位GluA1的磷酸化。此外，STIM2还促进cAMP依赖的GluA1的表面递送。STIMs(哺乳动物中的STIM1和STIM2)是驻留在内质网(ER)中的跨膜蛋白，调节由存储操作的钙内流(SOCE)。Stims在大脑中的功能才刚刚开始被探索，SOCE在神经细胞中的相关性还在争论中。在这里，我们认为STIM2是兴奋性突触的中心组织者。STIM2影响树突棘的形成，并影响兴奋性神经元的基础突触传递，但不影响其准分子STIM1。我们进一步证明，STIM2对于依赖cAMP/PKA的AMPA受体(AMPAR)亚单位GluA1的磷酸化是必不可少的。CAMP可触发STIM2向ER-质膜(PM)接触部位的快速迁移，促进GluA1向这些ER-PM连接部位的募集，并促进STIM2在树突棘中的定位。生化和成像数据都表明，STIM2通过以不依赖于SOCE的方式将PKA偶联到AMPAR来调节GluA1的磷酸化。与STIM2在调节AMPAR磷酸化中的中心作用一致，STIM2通过对胞吐和内吞的综合作用促进cAMP依赖的GluA1的表面递送。总之，我们的结果指出了一种独特的突触可塑性机制，这种机制是由STIM2信号复合体在ER-PM接触部位的动态组装驱动的。
STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum and regulate store-operated Ca2+ entry. STIM2 mediates cAMP/PKA-dependent phosphorylation of the AMPA receptor subunit GluA1 in excitatory neurons. In addition, STIM2 promotes cAMP-dependent surface delivery of GluA1. STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum (ER) and regulate store-operated Ca2+ entry (SOCE). The function of STIMs in the brain is only beginning to be explored, and the relevance of SOCE in nerve cells is being debated. Here we identify STIM2 as a central organizer of excitatory synapses. STIM2, but not its paralogue STIM1, influences the formation of dendritic spines and shapes basal synaptic transmission in excitatory neurons. We further demonstrate that STIM2 is essential for cAMP/PKA-dependent phosphorylation of the AMPA receptor (AMPAR) subunit GluA1. cAMP triggers rapid migration of STIM2 to ER–plasma membrane (PM) contact sites, enhances recruitment of GluA1 to these ER-PM junctions, and promotes localization of STIM2 in dendritic spines. Both biochemical and imaging data suggest that STIM2 regulates GluA1 phosphorylation by coupling PKA to the AMPAR in a SOCE-independent manner. Consistent with a central role of STIM2 in regulating AMPAR phosphorylation, STIM2 promotes cAMP-dependent surface delivery of GluA1 through combined effects on exocytosis and endocytosis. Collectively our results point to a unique mechanism of synaptic plasticity driven by dynamic assembly of a STIM2 signaling complex at ER-PM contact sites.