Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity
Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity
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DOI：
10.1074/jbc.272.27.16713
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发表时间：
1997-07-04
影响因子：
4.8
通讯作者：
Lazdunski, M
中科院分区：
文献类型：
--
作者：
Romey, G;Attali, B;Lazdunski, M
非常缓慢地激活延迟整流器 K+ 通道 I-Ks 对于控制心脏动作电位的复极相和内耳 K+ 稳态至关重要。 I-Ks 通道是通过两种跨膜蛋白 KvLQT1 和 MinK 的组装形成的。 KvLQT1 突变与长 QT 综合征相关，该综合征会导致晕厥、猝死以及耳聋。在这里，我们展示了离子通道形成亚基之间的一种新的关联模式，即 MinK 的细胞质 C 末端直接与 KvLQT1 的孔区域相互作用。这种相互作用将 KvLQT1 通道电导从 7.6 皮西降低到 0.58 皮西。然而，由于 MinK 还揭示了大量先前沉默的 KvLQT1 通道 (x 60)，因此总体效果是宏观 K+ 电流大幅增加 (x 4)。与 KvLQT1/MinK 关联相关的构象变化会产生非常缓慢且复杂的激活动力学，而在失活过程中没有太多改变。 MinK 引起的变化在重复电刺激后 K+ 通道活性的发展中具有重要的调节作用，特别是对心动过速的影响。
The very slowly activating delayed rectifier K+ channel I-Ks is essential for controlling the repolarization phase of cardiac action potentials and K+ homeostasis in the inner ear. The I-Ks channel is formed via the assembly of two transmembrane proteins, KvLQT1 and MinK. Mutations in KvLQT1 are associated with a long QT syndrome that causes syncope and sudden death and also with deafness. Here, we show a new mode of association between ion channel forming subunits in that the cytoplasmic C-terminal end of MinK interacts directly with the pore region of KvLQT1. This interaction reduces KvLQT1 channel conductance from 7.6 to 0.58 picosiemens. However, because MinK also reveals a large number of previously silent KvLQT1 channels (x 60), the overall effect is a large increase (x 4) in the macroscopic K+ current. Conformational changes associated with the KvLQT1/MinK association create very slow and complex activation kinetics without much alteration in the deactivation process. Changes induced by MinK have an essential regulatory role in the development of this K+ channel activity upon repetitive electrical stimulation with a particular interest in tachycardia.