Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.
Control of Ca2+ Influx and Calmodulin Activation by SK-Channels in Dendritic Spines.
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DOI：
10.1371/journal.pcbi.1004949
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发表时间：
2016-05
影响因子：
4.3
通讯作者：
Mellor JR
中科院分区：
文献类型：
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作者：
Griffith T;Tsaneva-Atanasova K;Mellor JR
Hebbian突触可塑性的关键触发因素是Ca2+流入突触后树突棘。由nmda受体（NMDAR）和电压门控Ca2+通道（VGCC）激活引起的[Ca2+]增加的幅度被认为是通过钙调蛋白等Ca2+敏感酶的差异激活来决定突触可塑性的幅度和方向。Ca2+内流由Ca2+激活的K+通道（sk通道）负调控，K+通道反过来被神经调节剂如乙酰胆碱抑制。然而，sk通道控制突触可塑性诱导的确切机制尚不清楚。利用理想的、但生物物理上合理的树突脊柱内Ca2+和钙调蛋白动力学的三维模型，我们表明，sk通道在与诱导spike时间依赖的可塑性相关的神经元放电模式中特异性地调节钙调蛋白激活。sk通道的激活和随后通过NMDARs和l型VGCCs的Ca2+内流的减少导致钙调素（CaM）激活的数量级下降，为突触可塑性诱导的有效门控提供了一种机制。这为神经调节剂调节突触可塑性提供了一个共同的机制。突触后Ca2+内流激活钙调蛋白和CaMKII，从而触发细胞可塑性或联想可塑性。Ca2+通过电压依赖性NMDA受体和Ca2+通道的内流由Ca2+激活的K+通道（sk通道）调节，提供突触后[Ca2+]的负反馈调节。利用树突棘内Ca2+和钙调蛋白动力学的三维建模，我们表明Ca2+内流和钙调蛋白激活之间的非线性关系赋予sk通道“门”钙调蛋白激活的能力，从而诱导Hebbian突触可塑性。由于sk -通道受到包括乙酰胆碱和去甲肾上腺素在内的几种神经调节剂受体的抑制，因此sk -通道对突触可塑性的门控可能是神经调节剂控制突触可塑性诱导的一种共同机制。
The key trigger for Hebbian synaptic plasticity is influx of Ca2+ into postsynaptic dendritic spines. The magnitude of [Ca2+] increase caused by NMDA-receptor (NMDAR) and voltage-gated Ca2+ -channel (VGCC) activation is thought to determine both the amplitude and direction of synaptic plasticity by differential activation of Ca2+ -sensitive enzymes such as calmodulin. Ca2+ influx is negatively regulated by Ca2+ -activated K+ channels (SK-channels) which are in turn inhibited by neuromodulators such as acetylcholine. However, the precise mechanisms by which SK-channels control the induction of synaptic plasticity remain unclear. Using a 3-dimensional model of Ca2+ and calmodulin dynamics within an idealised, but biophysically-plausible, dendritic spine, we show that SK-channels regulate calmodulin activation specifically during neuron-firing patterns associated with induction of spike timing-dependent plasticity. SK-channel activation and the subsequent reduction in Ca2+ influx through NMDARs and L-type VGCCs results in an order of magnitude decrease in calmodulin (CaM) activation, providing a mechanism for the effective gating of synaptic plasticity induction. This provides a common mechanism for the regulation of synaptic plasticity by neuromodulators. Hebbian or associative plasticity is triggered by postsynaptic Ca2+ influx which activates calmodulin and CaMKII. The influx of Ca2+ through voltage-dependent NMDA receptors and Ca2+ channels is regulated by Ca2+ -activated K+ channels (SK-channels) providing negative feedback regulation of postsynaptic [Ca2+]. Using 3-dimensional modeling of Ca2+ and calmodulin dynamics within dendritic spines we show that the non-linear relationship between Ca2+ influx and calmodulin activation endows SK-channels with the ability to “gate” calmodulin activation and therefore the induction of Hebbian synaptic plasticity. Since SK-channels are inhibited by several neuromodulator receptors including acetylcholine and noradrenaline, the gating of synaptic plasticity by SK-channels could represent a common mechanism by which neuromodulators control the induction of synaptic plasticity.