Pharmacological comparison of native mitochondrial KATP channels with molecularly defined surface KATP channels
Pharmacological comparison of native mitochondrial KATP channels with molecularly defined surface KATP channels
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DOI：
10.1124/mol.59.2.225
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发表时间：
2001-02-01
影响因子：
3.6
通讯作者：
Seharaseyon, J
中科院分区：
文献类型：
--
作者：
Liu, YG;Ren, GF;Seharaseyon, J
许多哺乳动物细胞有两种不同类型的ATP敏感钾通道：经典的表面膜通道（sK(ATP)）和线粒体内膜通道（mitoK(ATP)）。心脏mitoK（ATP）通道在缺血预处理中起着关键作用，因此是有趣的药物靶点。不幸的是，mitoK（ATP）通道的分子结构是未知的，与sK（ATP）通道相反，sK（ATP）通道由一个成孔亚基（Kir6.1或Kir6.2）和一个磺酰脲受体（SUR1， SUR2A或SUR2B）组成。为了探索mitoK（ATP）通道的分子组成，我们比较了天然心脏mitoK（ATP）通道与在人胚胎肾293细胞中异种表达的分子定义的sK（ATP）通道的药理学。利用线粒体氧化法测定兔心室肌细胞mitoK（ATP）通道活性，我们发现pinacidil和diazoxide可以打开mitoK（ATP）通道，而P-1075则不能。另一方面，5-羟基癸酸（5HD），而不是HMR-1098，阻断mitoK（ATP）通道。虽然pinacidil是表达的sK（ATP）通道的非选择性激活剂，但二氮氧化物不会打开Kir6.1/SUR2A, Kir6.2/SUR2A（心脏sK（ATP）通道的已知组分）或Kir6.2/SUR2B形成的通道。P-1075激活了除Kir6.1/SUR1通道外的所有K-ATP通道。格列本脲能有效阻断所有的sK（ATP）通道，但5HD仅阻断由SUR1/Kir6.1或Kir6.2形成的通道（IC(50)s分别为66和81 muM）。这种效力与阻断mitoK（ATP）通道相似（IC50 = 95 muM）。此外，HMR-1098有效阻断Kir6.2/SUR2A通道（IC50 = 1.5 muM），但阻断Kir6.1/SUR1通道的效力低67倍（IC50 = 100 muM）。我们的研究结果表明，mitoK（ATP）通道在其药理学特征上与Kir6.1/SUR1 sK（ATP）通道非常相似。
Many mammalian cells have two distinct types of ATP-sensitive potassium (K-ATP) channels: the classic ones in the surface membrane (sK(ATP)) and others in the mitochondrial inner membrane (mitoK(ATP)). Cardiac mitoK(ATP) channels play a pivotal role in ischemic preconditioning, and thus represent interesting drug targets. Unfortunately, the molecular structure of mitoK(ATP) channels is unknown, in contrast to sK(ATP) channels, which are composed of a pore-forming subunit (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1, SUR2A, or SUR2B). As a means of probing the molecular makeup of mitoK(ATP) channels, we compared the pharmacology of native cardiac mitoK(ATP) channels with that of molecularly defined sK(ATP) channels expressed heterologously in human embryonic kidney 293 cells. Using mitochondrial oxidation to index mitoK(ATP) channel activity in rabbit ventricular myocytes, we found that pinacidil and diazoxide open mitoK(ATP) channels, but P-1075 does not. On the other hand, 5-hydroxydecanoic acid (5HD), but not HMR-1098, blocks mitoK(ATP) channels. Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B. P-1075 activated all the K-ATP channels, except Kir6.1/SUR1 channels. Glybenclamide potently blocked all sK(ATP) channels, but 5HD only blocked channels formed by SUR1/Kir6.1 or Kir6.2 (IC(50)s of 66 and 81 muM, respectively). This potency is similar to that for block of mitoK(ATP) channels (IC50 = 95 muM). In addition, HMR-1098 potently blocked Kir6.2/SUR2A channels (IC50 = 1.5 muM), but was 67 times less potent in blocking Kir6.1/SUR1 channels (IC50 = 100 muM). Our results demonstrate that mitoK(ATP) channels closely resemble Kir6.1/SUR1 sK(ATP) channels in their pharmacological profiles.