The mitochondrial K-ATP channel as a receptor for potassium channel openers
The mitochondrial K-ATP channel as a receptor for potassium channel openers
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DOI：
10.1074/jbc.271.15.8796
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发表时间：
1996-04-12
影响因子：
4.8
通讯作者：
Schindler, PA
中科院分区：
文献类型：
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作者：
Garlid, KD;Paucek, P;Schindler, PA
线粒体K-ATP通道的生物化学性质与质膜K-ATP通道的生物化学性质非常相似，包括低浓度ATP和格列本脲的抑制（Paucek，P.，Mironova，G.，Mahdi，F.，Beavis，A，D，Woldegiorgis，G，，and Garlid，K. D，（1992）J，Biol，Chem.267，26062-26069），质膜K-ATP通道对称为K+通道开放剂的药物家族高度敏感，这提出了线粒体K-ATP通道是否对这些药物同样敏感的问题，Ne通过测量完整大鼠肝线粒体和含K+的脂质体中的K+通量来解决这个问题。从大鼠肝脏和牛心线粒体中纯化的ATP通道，K+通道开放剂完全逆转了这两个系统中ATP对K+通量的抑制，在脂质体中，二氮嗪恢复了ATP抑制的K+通量（K-1/2 = 0.4 μ M），色满卡林（K-1/2 = 1 μ M）和两种开发性色满卡林类似物，EMD 60480和EMD 57970（K-1/2 = 6 nM），在完整线粒体中观察到相似的K-1/2值，这些效力完全在质膜K-ATP通道观察到的范围内，我们还比较了这些K+通道开放剂对从牛心肌细胞纯化的质膜K-ATP通道的效力。来自心肌线粒体的K-ATP通道对二氮嗪的敏感性比来自心肌肌膜的通道高2000倍，表明两种不同的受体亚型共存于心肌细胞内。Ne建议线粒体K-ATP通道是一种重要的细胞内受体，在考虑K+通道开放剂的药理学时应考虑到这一点。
The biochemical properties of the mitochondrial K-ATP channel are very similar to those of plasma membrane K-ATP channels, including inhibition by low concentrations of ATP and glyburide (Paucek, P,, Mironova, G., Mahdi, F., Beavis, A, D,, Woldegiorgis, G,, and Garlid, K. D, (1992) J, Biol, Chem. 267, 26062-26069), Plasma membrane K-ATP channels are highly sensitive to the family of drugs known as K+ channel openers, raising the question whether mitochondrial K-ATP channels are similarly sensitive to these agents, Ne addressed this question by measuring K+ flux in intact rat liver mitochondria and in liposomes containing K-ATP channels purified from rat liver and beef heart mitochondria, K+ channel openers completely reversed ATP inhibition of K+ flux in both systems, In Liposomes, ATP-inhibited K+ flux was restored by diazoxide (K-1/2 = 0.4 mu M), cromakalim (K-1/2 = 1 mu M), and two developmental cromakalim analogues, EMD60480 and EMD57970 (K-1/2 = 6 nM), Similar K-1/2 values were observed in intact mitochondria, These potencies are well within the range observed with plasma membrane K-ATP channels, We also compared the potencies of these K+ channel openers on the plasma membrane K-ATP channel purified from beef heart myocytes, The K-ATP channel from cardiac mitochondria is 2000-fold more sensitive to diazoxide than the channel from cardiac sarcolemma, indicating that two distinct receptor subtypes coexist within the myocyte. Ne suggest that the mitochondrial K-ATP channel is an important intracellular receptor that should be taken into account in considering the pharmacology of K+ channel openers.