Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons.
Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons.
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DOI：
10.1523/jneurosci.4742-09.2009
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发表时间：
2009-12-09
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影响因子：
--
通讯作者：
Levitan ES
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文献类型：
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作者：
Putzier I;Kullmann PH;Horn JP;Levitan ES
Cav1.3(α1D)L型钙通道与黑质(SN)、多巴胺(DA)神经元起搏和帕金森病易感性有关。这些效应可能与Cav1.3通道在阈值下膜电位时产生的去极化电流和胞浆内钙升高有关。然而，Caf Cav 1.3通道的钙选择性是必需的这一假设尚未得到检验。本研究用动态钳制产生的虚拟通道代替二氢吡啶-尼莫地平阻断的天然通道，探讨了SNDA神经元驱动幼年大鼠脑片起搏活动的L型钙通道的特性。令人惊讶的是，模拟天然和重组Cav1.3通道的虚拟L型通道支持起搏器活动，即使动态钳制电流不是由钙携带的。这种效应是特殊的，因为紧张性电流注入、虚拟非选择性漏通道或虚拟N-甲基-D-天冬氨酸受体不能恢复起搏器的活动，它们与L型通道在IV曲线上共享一个负斜率电导区域。改变虚通道显示起搏器活动的产生依赖于DA神经元L型通道的电压依赖性，而激活动力学和翻转电位不是关键参数。虚拟L类型的通道还支持慢振荡电位(SOP)和在诱发突发时增强的放电频率。因此，Cav1.3通道电压依赖性，而不是钙离子选择性，推动了SN DA神经元的起搏活动并放大了猝发。
Cav1.3 (α1D) L-type Ca2+ channels have been implicated in substantia nigra (SN) dopamine (DA) neuron pacemaking and vulnerability to Parkinson’s disease. These effects may arise from the depolarizing current and cytoplasmic Ca2+ elevation produced by Cav1.3 channels at subthreshold membrane potentials. However, the assumption that the Ca2+ selectivity of Caf Cav 1.3 channels is essential has not been tested. In this study the properties of SN DA neuron L-type Ca2+ channels responsible for driving pacemaker activity in juvenile rat brain slices were probed by replacing native channels blocked with the dihydropyridine nimodipine with virtual channels generated by dynamic clamp. Surprisingly, virtual L-type channels that mimic native and recombinant Cav1.3 channels supported pacemaker activity even though dynamic clamp currents are not carried by Ca2+. This effect is specific because pacemaker activity could not be restored by tonic current injection, virtual nonselective leak channels or virtual NMDA receptors, which share with L-type channels a negative slope conductance region in their IV curve. Altering virtual channels showed that the production of pacemaker activity depended on the characteristic voltage dependence of DA neuron L-type channels, while activation kinetics and reversal potential were not critical parameters. Virtual L-type channels also supported slow oscillatory potentials (SOPs) and enhanced firing rate during evoked bursts. Thus, Cav1.3 channel voltage dependence, rather than Ca2+ selectivity, drives pacemaker activity and amplifies bursts in SN DA neurons.