Calmodulin priming: Nuclear translocation of a calmodulin complex and the memory of prior neuronal activity
Calmodulin priming: Nuclear translocation of a calmodulin complex and the memory of prior neuronal activity
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DOI：
10.1073/pnas.211563998
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发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Tsien, RW
中科院分区：
文献类型：
--
作者：
Mermelstein, PG;Deisseroth, K;Tsien, RW
神经元核在信息处理中起着至关重要的作用，但它是否支持与突触相媲美的成对脉冲促进等计算功能尚不清楚。钙调素(CaM)依赖于Ca~(2+)向胞核的移动是对Ca~(2+)通过L通道进入核内的高度反应，并通过CaM敏感的激酶磷酸化促进转录因子CREB(cAMP反应元件结合蛋白)的激活，我们表征了这种CaM易位的关键特征及其在核信号转导中的可能作用。在刺激开始的15个S内，核钙调素升高，先于海马锥体神经元CREB磷酸化的第一个迹象。在小脑颗粒细胞、新皮质神经元和齿状回颗粒细胞中也观察到去极化诱导的核CaM升高。CaM的核转位不能被肌动蛋白细丝或微管破坏，也不能通过用thapsigargin排空内质网钙库来阻止。荧光标记的CaM与钙/CaM结合肽M13融合可阻止其易位，这表明核CaM的聚集依赖于与内源性钙/CaM结合蛋白的结合。为了确定核[CaM]的增加是否会影响随后的核信号处理，我们比较了两个连续的去极化刺激的反应。在弱的“启动”刺激导致CaM易位后，由随后的刺激引起的CREB的磷酸化明显加快，对钙离子升高更加敏感，对通过L类通道的钙离子内流的依赖性较低。CaM易位不仅支持向核内快速传递信号，而且还可以为重复神经活动的易化效应提供“记忆”，这可以在改变的磷酸化CREB动力学和钙通道依赖中看到。
The neuronal nucleus plays a vital role in information processing, but whether it supports computational functions such as paired-pulse facilitation, comparable to synapses, is unclear. Ca2+-dependent movement of calmodulin (CaM) to the nucleus is highly responsive to Ca2+ entry through L-type channels and promotes activation of the transcription factor CREB (CAMP-responsive element binding protein) through phosphorylation by CaM-sensitive kinases, We characterized key features of this CaM translocation and its possible role in facilitation of nuclear signaling. Nuclear CaM was elevated within 15 s of stimulus onset, preceding the first signs of CREB phosphorylation in hippocampal pyramidal neurons. Depolarization-induced elevation of nuclear CaM also was observed in cerebellar granule cells, neocortical neurons, and dentate gyrus granule cells. Nuclear translocation of CaM was not blocked by disruption of actin filaments or microtubules, or by emptying endoplasmic reticulum Ca2+ stores with thapsigargin. Translocation of fluorescently tagged CaM was prevented by fusing it with the Ca2+/CaM binding peptide M13, suggesting that nuclear CaM accumulation depends on association with endogenous Ca2+/CaM binding proteins. To determine whether increased nuclear [CaM] might influence subsequent nuclear signal processing, we compared responses to two consecutive depolarizing stimuli. After a weak "priming" stimulus that caused CaM translocation, CREB phosphorylation caused by a subsequent stimulus was significantly faster, more sensitive to Ca2+ elevation, and less specifically dependent on Ca2+ influx through L-type channels. CaM translocation not only supports rapid signaling to the nucleus, but also could provide a "memory" for facilitatory effects of repeated neural activity, seen in altered phosphorylated CREB dynamics and Ca2+ channel dependence.