MODULATION OF ATP-SENSITIVE K+ CHANNELS IN SKELETAL-MUSCLE BY INTRACELLULAR PROTONS
MODULATION OF ATP-SENSITIVE K+ CHANNELS IN SKELETAL-MUSCLE BY INTRACELLULAR PROTONS
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DOI：
10.1038/343375a0
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发表时间：
1990-01-25
期刊：
影响因子：
64.8
通讯作者：
DAVIES, NW
中科院分区：
文献类型：
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作者：
DAVIES, NW
自从在心肌1中发现三磷酸腺苷敏感性钾通道以来，已经在胰腺β细胞2、骨骼肌3、平滑肌4和中枢神经元5中发现了钾通道。胞内ATP的存在抑制了KATP通道的活动。它们的广泛分布表明它们可能具有重要的生理作用，这些作用可能因组织而异。在肌肉细胞中，K+通道的作用是控制膜的兴奋性和动作电位的持续时间。在缺氧性心肌中，KATP通道被认为是导致动作电位缩短的原因，有研究认为，代谢衰竭过程中ATP浓度的下降会增加骨骼肌中KATP通道的活性，这可能会降低兴奋性。但是，肌肉细胞内的ATP浓度被肌酸磷酸缓冲到5-10 mM，即使在持续的运动中也几乎没有变化。这一浓度远高于在心肌(0.1 mM)1或骨骼肌(0.14 mM)9中半阻断KATP通道电流所需的细胞内ATP浓度，这表明在完整的肌肉中KATP通道的开放概率通常很低。因此，可能存在一些额外的调节KATP通道活性的方法，如与ATP10-12以外的核苷酸的结合。在这里，我提出的证据表明，细胞内pH(Phi)的降低显著降低了ATP对青蛙骨骼肌离断斑块中这些通道的抑制作用。由于持续的肌肉活动可以在KATP通道对PHi最敏感的范围内降低PHi近1个单位13，14，因此在生理条件下，骨骼肌中这些通道的活动可能是由细胞内质子调节的。
SINCE their discovery in cardiac muscle1, ATP-sensitive K+(KATP) channels have been identified in pancreatic β-cells2, skeletal muscle3, smooth muscle4and central neurons5. The activity of KATPchannels is inhibited by the presence of cytosolic ATP. Their wide distribution indicates that they could have important physiological roles that may vary between tissues. In muscle cells the role of K+channels is to control membrane excitability and the duration of the action potential. In anoxic cardiac ventricular muscle KATPchannels are believed to be responsible for shortening the action potential6, and it has been proposed that a fall in ATP concentration during metabolic exhaustion increases the activity of KATPchannels in skeletal muscle7, which may reduce excitability. But the intracellular concentration of ATP in muscle is buffered by creatine phosphate to 5–10 mM, and changes little, even during sustained activity8. This concentration is much higher than the intracellular ATP concentration required to half block the KATP-channel current in either cardiac muscle (0.1 mM)1or skeletal muscle (0.14 mM)9, indicating that the open-state probability of KATPchannels is normally very low in intact muscle. So it is likely that some additional means of regulating the activity of KATP channels exists, such as the binding of nucleotides other than ATP10–12. Here I present evidence that a decrease in intracellular pH (pHi) markedly reduces the inhibitory effect of ATP on these channels in excised patches from frog skeletal muscle. Because sustained muscular activity can decrease pHiby almost 1 unit13,14in the range at which KATPchannels are most sensitive to pHiit is likely that the activity of these channels in skeletal muscle is regulated by intracellular protons under physiological conditions.