Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels
Contrasting biophysical and pharmacological properties of T-type and R-type calcium channels
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DOI：
10.1016/s0028-3908(97)00086-5
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发表时间：
1997-07-01
影响因子：
4.7
通讯作者：
Tsien, RW
中科院分区：
文献类型：
--
作者：
Randall, AD;Tsien, RW
与其他类型的电压门控钙通道相比，T型和R型通道的分子基础还不清楚。为了便于与克隆的Ca 2+通道亚基进行比较，我们对未分化NG 108 -15细胞的T型电流和小脑颗粒神经元的R型电流的特性进行了系统的分析。在相同的记录条件下，发现它们的生物物理和药理学特征存在显著差异。T型通道在比R型通道负约25 mV的电位下被激活;然而，T型通道需要比R型通道负约15 mV的电位才能被激活。因此，T型通道在描述失活和激活的曲线之间显示出大得多的重叠，使得它们更适合于产生持续的Ca 2+进入以支持分泌或起搏器活性。相比之下，R型通道不具备提供稳定电流的能力，但非常能够提供Ca 2+流入的瞬时浪涌。在响应一系列越来越强的去极化T型和R型钙离子通道引起了非常不同的动力学模式。T型电流记录在R型电流没有发现的特征模式中彼此交叉。这些生物物理的区别是独立的绝对膜电位，因此，补充传统分类的T-和R-型钙离子通道的低电压和高电压激活。R型通道失活的速度比T型通道快约8倍，在模拟动作电位过程中产生二价阳离子流入的后果明显。药理学比较显示了额外的对比。R型电流对Ω-Aga IIIA阻断有反应，但对尼莫地平无反应，而T型电流则相反。这两种通道类型均被非二氢吡啶化合物米贝拉地尔强效抑制。在所有方面检查，R-型电流是类似的电流来自表达的α（1 E）亚基，而T-型电流没有。(C)1997 Elsevier Science Ltd.
In contrast to other kinds of voltage-gated Ca2+ channels, the underlying molecular basis of T-type and R-type channels is not well-understood. To facilitate comparisons with cloned Ca2+ channel subunits, we have carried out a systematic analysis of the properties of T-type currents in undifferentiated NG108-15 cells and R-type currents in cerebellar granule neurons. Marked differences were found in their biophysical and pharmacological features under identical recording conditions. T-type channels became activated at potentials approximately 25 mV more negative than R-type channels; however, T-type channels required potentials approximately 15 mV less negative than R-type channels to be available. Accordingly, T-type channels display a much larger overlap between the curves describing inactivation and activation, making them more suitable for generating sustained Ca2+ entry in support of secretion or pacemaker activity. In contrast, R-type channels are not equipped to provide a steady current, but are very capable of supplying transient surges of Ca2+ influx. In response to a series of increasingly strong depolarizations T-type and R-type Ca2+ channels gave rise to very different kinetic patterns. T-type current records crossed each other in a characteristic pattern not found for R-type currents. These biophysical distinctions were independent of absolute membrane potential and were, therefore, complementary to the conventional categorization of T- and R-type Ca2+ channels as low- and high voltage activated. R-type channels deactivated approximately eight-fold more quickly than T-type channels, with clear consequences for the generation of divalent cation influx during simulated action potentials. Pharmacological comparisons revealed additional contrasts. R-type current was responsive to block by omega-Aga IIIA but not nimodipine, while the opposite was true for T-type current. Both channel types were potently inhibited by the non-dihydropyridine compound mibefradil. In all respects examined, R-type currents were similar to currents derived from expression of the alpha(1E) subunit whereas T-type currents were not. (C) 1997 Elsevier Science Ltd.