Cu2+, Co2+, and Mn2+ modify the gating kinetics of high-voltage-activated Ca2+ channels in rat palaeocortical neuronsd
Cu2+, Co2+, and Mn2+ modify the gating kinetics of high-voltage-activated Ca2+ channels in rat palaeocortical neuronsd
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DOI：
10.1007/s00232-003-0614-2
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发表时间：
2003-10-01
影响因子：
2.4
通讯作者：
Magistretti, J
中科院分区：
文献类型：
--
作者：
Castelli, L;Tanzi, F;Magistretti, J
利用膜片钳技术研究了三种二价金属阳离子（Mn2+、Co2+和Cu2+）对大鼠梨状皮质急性解离锥体神经元高压激活（HVA） Ca2+电流的影响。Cu2+、Mn2+和Co2+阻断Ba2+ (I-Ba)传导的高压电流，IC50分别为920 nM、58 muM和65 muM。此外，在应用非饱和浓度的三种阳离子后，剩余电流的激活动力学比控制I-Ba慢得多。因此，被阻断阳离子消除的电流分数通常在其早期阶段表现出异常快速的瞬态衰变。后一种现象被证明是减法伪象，因为所研究的构成总HVA电流的药理学成分（L-、N-、P/Q-和r型）都没有显示出类似的快速早期衰减：因此，剩余电流的缓慢激活动力学不是由于快速激活/失活成分的优先抑制，而是阻滞剂阳离子的真正减慢作用。在整个电位范围内（高达+30 mV）， Mn2+、Co2+和Cu2+引起的i - ba振幅抑制百分比是电压无关的，因此IBa激活动力学的减慢不是由于电压和时间依赖的阻断缓解机制。此外，Mn2+、Co2+和Cu2+在复极化时显著降低了I-Ba的失活速度，这也不符合依赖于去极化的解锁机制。以上结果表明：1)Cu2+在大鼠古皮质神经元中是一种特别有效的HVA Ca2+通道阻滞剂；2) Mn2+， Co2+和Cu2+除了对HVA Ca2+通道施加阻断作用外，还可以通过直接干扰通道状态转变来改变Ca2+电流的激活和失活动力学。
The effects of three divalent metal cations (Mn2+, Co2+, and Cu2+) on high-voltage-activated (HVA) Ca2+ currents were studied in acutely dissociated pyramidal neurons of rat piriform cortex using the patch-clamp technique. Cu2+, Mn2+, and Co2+ blocked HVA currents conducted by Ba2+ (I-Ba) with IC50 of similar to920 nM, similar to58 muM, and similar to65 muM, respectively. Additionally, after application of non-saturating concentrations of the three cations, residual currents activated with substantially slower kinetics than control I-Ba. As a consequence, the current fraction abolished by the blocking cations typically displayed, in its early phase, an unusually fast-decaying transient. The latter phenomenon turned out to be a subtraction artifact, since none of the pharmacological components (L-, N-, P/Q-, and R-type) that constitute the total HVA currents under study showed a similarly fast early decay: hence, the slow activation kinetics of residual currents was not due to the preferential inhibition of a fast-activating/inactivating component, but rather to a true slowing effect of the blocker cations. The percent I-Ba-amplitude inhibition caused by Mn2+, Co2+, and Cu2+ was voltage-independent over the whole potential range explored (up to +30 mV), hence the slowing of IBa activation kinetics was not due to a mechanism of voltage- and time-dependent relief from block. Moreover, Mn2+, Co2+, and Cu2+ significantly reduced I-Ba deactivation speed upon repolarization, which also is not compatible with a depolarization-dependent unblocking mechanism. The above results show that 1) Cu2+ is a particularly potent HVA Ca2+-channel blocker in rat palaeocortical neurons; and 2) Mn2+, Co2+, and Cu2+, besides exerting a blocking action on HVA Ca2+-channels, also modify Ca2+-current activation and deactivation kinetics, most probably by directly interfering with channel-state transitions.