A mechanism for synaptic frequency detection through autophosphorylation of Cam kinase II
A mechanism for synaptic frequency detection through autophosphorylation of Cam kinase II
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DOI：
10.1016/s0006-3495(96)79821-1
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发表时间：
1996-06-01
影响因子：
3.4
通讯作者：
Albers, RW
中科院分区：
文献类型：
--
作者：
Dosemeci, A;Albers, RW
本文根据CaM激酶Ⅱ的下列特性提出了一个调节CaM激酶Ⅱ的模型：1）全酶由8-12个亚基组成，每个亚基具有相同的自磷酸化位点：2）一组位点（A位点）的自磷酸化需要Ca ~（2+）的存在，并使一个亚基在Ca ~（2+）去除后保持活性; 3）另一组位点（B位点）的自磷酸化仅在除去Ca 2+后发生，但需要全酶内阈值数量的A位点的预先磷酸化。由于B位点磷酸化抑制Ca 2 +/钙调素结合，我们提出，对于一个给定的亚基，磷酸化的B网站之前，A网站防止随后的磷酸化在A网站，从而锁定该亚基在一个非活性状态。该模型预测，由Ca 2+激活的阈值将启动“自磷酸化阶段”。一旦开始，全酶内自磷酸化将继续进行，在高[Ca 2 +]时期在A位点，在低[Ca 2 +]时期在B位点。在“饱和”时，即当每个亚基在B位点上被磷酸化时，磷酸化的A位点的数量以及因此激酶活性将反映在自磷酸化阶段期间发生的高[Ca 2 +]时期与低[Ca 2 +]时期的相对持续时间。使用设计来模拟上述机制的计算机程序，我们表明，最终状态的磷酸化的阵列的钙调蛋白激酶II分子可以敏感的时间模式的钙离子脉冲。我们推测，这样的机制可能允许阵列的钙调蛋白激酶II分子在突触后密度作为突触频率探测器参与设定的方向和水平的突触修饰。
A model for the regulation of CaM kinase II is presented based on the following reported properties of the molecule: 1) the holoenzyme is composed of 8-12 subunits, each with the same set of autophosphorylation sites; 2) autophosphorylation at one group of sites (A sites) requires the presence of Ca2+ and causes a subunit to remain active following the removal of Ca2+; 3) autophosphorylation at another group of sites (B sites) occurs only after the removal of Ca2+ but requires prior phosphorylation of a threshold number of A sites within the holoenzyme. Because B-site phosphorylation inhibits Ca2+/calmodulin binding, we propose that, for a given subunit, phosphorylation of a B site before an A site prevents subsequent phosphorylation at the A site and thereby locks that subunit in an inactive state. The model predicts that a threshold activation by Ca2+ will initiate an ''autophosphorylation phase.'' Once started, intra-holoenzyme autophosphorylation will proceed, on A sites during periods of high [Ca2+] and on B sites during periods of low [Ca2+]. At ''saturation,'' that is when every subunit has been phosphorylated on a B site, the number of phosphorylated A sites and, therefore, the kinase activity will reflect the relative durations of periods of high [Ca2+] to periods of low [Ca2+] that occurred during the autophosphorylation phase. Using a computer program designed to simulate the above mechanism, we show that the ultimate state of phosphorylation of an array of CaM kinase II molecules could be sensitive to the temporal pattern of Ca2+ pulses. We speculate that such a mechanism may allow arrays of CaM kinase II molecules in postsynaptic densities to act as synaptic frequency detectors involved in setting the direction and level of synaptic modification.