IQ-motif proteins influence intracellular free ca2+ in hippocampal neurons through their interactions with calmodulin
IQ-motif proteins influence intracellular free ca2+ in hippocampal neurons through their interactions with calmodulin
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DOI：
10.1152/jn.00876.2007
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发表时间：
2008-01-01
影响因子：
2.5
通讯作者：
Waxham, M. Neal
中科院分区：
文献类型：
--
作者：
Kubota, Yoshihisa;Putkey, John A.;Waxham, M. Neal
钙调素(CaM)在细胞内钙调蛋白(CaM)升高后激活钙调素依赖的酶中起重要作用。然而，CaM的高细胞内浓度表明CaM具有作为钙缓冲的重要作用。神经颗粒素(Ng)是一种含IQ基序的小分子神经元蛋白，可促进钙离子从CaM中解离。在同时含有高浓度Ng和CaM的细胞中，如CA1锥体神经元，我们假设Ng加速钙离子从CaM中解离，降低了CaM的缓冲能力，从而形成了细胞内游离钙的瞬时动力学。我们使用一个建立在已知Ng生物化学基础上的数学模型检验了这一假设，并用文献中的钙离子成像数据证实了模拟结果。在不含Ca~(2+)排出机制的单室模型中，Ng增加了稳态游离Ca~(2+)。然而，在存在Ca~(2+)排出机制的情况下，Ng通过增加钙离子从CaM中解离的能力而加速了游离Ca~(2+)的衰变速度，而CaM又被Ca~(2+)排出。有趣的是，另一种神经元IQ基序蛋白PEP-19可以促进钙结合和钙调素的解离，似乎与Ng对游离钙的影响相反。因此，除了钙-CaM依赖的过程外，Ng还可能通过影响CaM的缓冲能力以及随后的游离钙水平来调节钙敏感酶。我们研究了Ng诱导的这些效应在突触可塑性诱导中的相对影响。
Calmodulin (CaM) is most recognized for its role in activating Ca2+-CaM-dependent enzymes following increased intracellular Ca2+. However, CaM's high intracellular concentration indicates CaM has the potential to play a significant role as a Ca2+ buffer. Neurogranin (Ng) is a small neuronal IQ-motif-containing protein that accelerates Ca2+ dissociation from CaM. In cells that contain high concentrations of both Ng and CaM, like CA1 pyramidal neurons, we hypothesize that the accelerated Ca2+ dissociation from CaM by Ng decreases the buffering capacity of CaM and thereby shapes the transient dynamics of intracellular free Ca2+. We examined this hypothesis using a mathematical model constructed on the known biochemistry of Ng and confirmed the simulation results with Ca2+ imaging data in the literature. In a single-compartment model that contains no Ca2+ extrusion mechanism, Ng increased the steady-state free Ca2+. However, in the presence of a Ca2+ extrusion mechanism, Ng accelerated the decay rate of free Ca2+ through its ability to increase the Ca2+ dissociation from CaM, which in turn becomes subject to Ca2+ extrusion. Interestingly, PEP-19, another neuronal IQ-motif protein that accelerates both Ca2+ association and dissociation from CaM, appears to have the opposite impact than that of Ng on free Ca2+. As such, Ng may regulate, in addition to the Ca2+ -CaM-dependent process, Ca2+- sensitive enzymes by influencing the buffering capacity of CaM and subsequently free Ca2+ levels. We examined the relative impact of these Ng-induced effects in the induction of synaptic plasticity.