Modulation of Cav2.1 channels by Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain
Modulation of Cav2.1 channels by Ca2+/calmodulin-dependent protein kinase II bound to the C-terminal domain
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DOI：
10.1073/pnas.0710213105
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发表时间：
2008-01-08
影响因子：
11.1
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Jiang, Xin;Lautermilch, Nathan J.;Catterall, William A.
钙/钙调蛋白依赖的蛋白激酶II(CaMKII)是突触后密度中突触反应的关键调节因子，但其在突触前神经元中的作用机制尚不完全清楚。在这里，我们发现CaMKII与电压门控钙通道(Ca-v)2.1相关联并对其进行调节，该通道传导P/Q型钙电流并启动递质释放。外源性和脑特异性的CaMKII抑制剂均可加速电压依赖性失活，引起电压依赖性失活的负移，并降低Ca(V)2.11通道的钙依赖易化。CaMKII的调节作用可被阻止与Ca(V)2.1通道结合的多肽减少，但不能被阻断催化活性的多肽减少，这表明调节作用是结合而不是磷酸化起作用的。我们的结果揭示了一个由Ca(V)2.1通道和CaMKII形成的信号复合体，它调节神经元上的P/Q型钙电流。我们提出了一个“效应检查点”模型，用于控制钙离子通道的功能适宜性，该模型依赖于与CaMKII、SNARE蛋白和其他钙信号效应分子的关联。这种调节机制在突触前神经末梢中很重要，其中Ca(V)2.1通道启动突触传递，而CaMKII对突触前可塑性具有非催化作用。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of synaptic responses in the postsynaptic density, but understanding of its mechanisms of action in the presynaptic neuron is incomplete. Here we show that CaMKII constitutively associates with and modulates voltage-gated calcium (Ca-v)2.1 channels that conduct P/Q type Ca2+ currents and initiate transmitter release. Both exogenous and brain-specific inhibitors of CaMKII accelerate voltage-dependent inactivation, cause a negative shift in the voltage dependence of inactivation, and reduce Ca2+-dependent facilitation of Ca(v)2.11 channels. The modulatory effects of CaMKII are reduced by a peptide that prevents binding to Ca(v)2.1 channels but not by a peptide that blocks catalytic activity, suggesting that binding rather than phosphorylation is responsible for modulation. Our results reveal a signaling complex formed by Ca(v)2.1 channels and CaMKII that regulates P/Q-type Ca2+ current in neurons. We propose an '' effector checkpoint '' model for the control of Ca2+ channel fitness for function that depends on association with CaMKII, SNARE proteins, and other effectors of Ca2+ signals. This regulatory mechanism would be important in presynaptic nerve terminals, where Ca(v)2.1 channels initiate synaptic transmission and CaMKII has noncatalytic effects on presynaptic plasticity.