A molecular link between activation and inactivation of sodium channels.
A molecular link between activation and inactivation of sodium channels.
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DOI：
10.1085/jgp.106.4.641
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发表时间：
1995-10
期刊：
影响因子：
--
通讯作者：
Horn R
中科院分区：
文献类型：
--
作者：
O'Leary ME;Chen LQ;Kallen RG;Horn R
一对酪氨酸残基，位于人心脏钠通道的第三和第四结构域之间的细胞质接头上，在失活的动力学和电压依赖性中起着关键作用。用谷氨酰胺（Y1494 Y1495/QQ）取代这些残基，而不是苯丙氨酸，几乎消除了去极化后从宏观电流衰减测量的失活时间常数的电压依赖性。稳态失活和失活恢复的电压依赖性也在YY/QQ通道中降低。钠通道激活和失活之间偶联的一个特征是去极化后失活发展延迟。这种延迟在野生型中可见，但在YY/QQ通道中缩短为-30 mV。在突变体中，在比-20 mV更负的电压下，激活的宏观动力学更快且电压依赖性更小。相比之下，失活动力学在比-70 mV更负的电压下在突变型和野生型通道之间没有显著差异。单通道测量显示，与野生型通道相比，YY/QQ通道在去极化后打开的延迟时间更短，电压依赖性更小;然而，YY/QQ通道的峰值打开概率没有受到显著影响。这些数据表明，参与激活和失活的速率常数在YY/QQ通道中改变。这些酪氨酸是激活电压传感器和失活门之间正常耦合所需的。这种耦合确保宏观失活速率在负电压下缓慢，而在更正的电压下加速。YY/QQ中偶联的破坏改变了激活和失活的微观速率。
A pair of tyrosine residues, located on the cytoplasmic linker between the third and fourth domains of human heart sodium channels, plays a critical role in the kinetics and voltage dependence of inactivation. Substitution of these residues by glutamine (Y1494Y1495/QQ), but not phenylalanine, nearly eliminates the voltage dependence of the inactivation time constant measured from the decay of macroscopic current after a depolarization. The voltage dependence of steady state inactivation and recovery from inactivation is also decreased in YY/QQ channels. A characteristic feature of the coupling between activation and inactivation in sodium channels is a delay in development of inactivation after a depolarization. Such a delay is seen in wild-type but is abbreviated in YY/QQ channels at -30 mV. The macroscopic kinetics of activation are faster and less voltage dependent in the mutant at voltages more negative than -20 mV. Deactivation kinetics, by contrast, are not significantly different between mutant and wild-type channels at voltages more negative than -70 mV. Single-channel measurements show that the latencies for a channel to open after a depolarization are shorter and less voltage dependent in YY/QQ than in wild-type channels; however the peak open probability is not significantly affected in YY/QQ channels. These data demonstrate that rate constants involved in both activation and inactivation are altered in YY/QQ channels. These tyrosines are required for a normal coupling between activation voltage sensors and the inactivation gate. This coupling insures that the macroscopic inactivation rate is slow at negative voltages and accelerated at more positive voltages. Disruption of the coupling in YY/QQ alters the microscopic rates of both activation and inactivation.