5-羟基癸酸酯和辅酶A是由内而外的斑块中天然肌膜KATP通道的抑制剂。,Biochimica et Biophysica Acta (BBA) - General Subjects

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5-羟基癸酸酯和辅酶A是由内而外的斑块中天然肌膜KATP通道的抑制剂。
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2009-11-26 , DOI: 10.1016/j.bbagen.2009.11.012
Xiantao Li ₁ , Markus Rapedius , Thomas Baukrowitz , Gong Xin Liu , D K Srivastava , Jürgen Daut , Peter J Hanley

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背景技术5-羟基癸酸酯（5-HD）会抑制预处理，因此被认为是线粒体ATP敏感K（+）（mitoK（ATP））通道的选择性抑制剂。但是，5-HD是线粒体外膜酰基辅酶A合成酶的底物，该酶催化以下反应：5HD + CoA + ATP-> 5-HD-CoA（5-hydroxydecanoyl-CoA）+ AMP +焦磷酸盐。我们旨在确定此反应的反应物或主要产物是否调节肌膜K（ATP）（sarcK（ATP））通道活性。方法测量从大鼠心室肌细胞切出的内外贴片中的单个sarcK（ATP）通道电流。此外，sarcK（ATP）通道的活动记录在全细胞配置或从表达Kir6.2 / SUR2A的卵母细胞切除的巨大的由内而外的补丁中。结果5-HD抑制（IC（50）约30 microM）K（ATP）通道活性，尽管仅存在（非抑制性）浓度的ATP。类似地，当0.2 microM ATP的抑制作用被1 microM油酰-CoA逆转时，随后应用5-HD阻断了通道活性，但在不存在ATP的情况下未见作用。此外，我们发现1 microM辅酶A（CoA）抑制了sarcK（ATP）通道。使用对“污染” CoA敏感度不高的巨型由内而外的补丁，我们发现Kir6.2 / SUR2A通道对5-HD-CoA不敏感。在完整的心肌细胞中，5-HD无法通过代谢抑制或利马卡林来逆转sarcK（ATP）通道激活。一般意义SarcK（ATP）通道被5-HD（假定存在ATP）和CoA抑制，但对5-HD-CoA不敏感。5-HD同样有效地“直接”抑制sarcK（ATP）和mitoK（ATP）通道。然而，

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5-Hydroxydecanoate and coenzyme A are inhibitors of native sarcolemmal KATP channels in inside-out patches.

BACKGROUND 5-Hydroxydecanoate (5-HD) inhibits preconditioning, and it is assumed to be a selective inhibitor of mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels. However, 5-HD is a substrate for mitochondrial outer membrane acyl-CoA synthetase, which catalyzes the reaction: 5HD + CoA + ATP --> 5-HD-CoA (5-hydroxydecanoyl-CoA) + AMP + pyrophosphate. We aimed to determine whether the reactants or principal product of this reaction modulate sarcolemmal K(ATP) (sarcK(ATP)) channel activity. METHODS Single sarcK(ATP) channel currents were measured in inside-out patches excised from rat ventricular myocytes. In addition, sarcK(ATP) channel activity was recorded in whole-cell configuration or in giant inside-out patches excised from oocytes expressing Kir6.2/SUR2A. RESULTS 5-HD inhibited (IC(50) approximately 30 microM) K(ATP) channel activity, albeit only in the presence of (non-inhibitory) concentrations of ATP. Similarly, when the inhibitory effect of 0.2 mM ATP was reversed by 1 microM oleoyl-CoA, subsequent application of 5-HD blocked channel activity, but no effect was seen in the absence of ATP. Furthermore, we found that 1 microM coenzyme A (CoA) inhibited sarcK(ATP) channels. Using giant inside-out patches, which are weakly sensitive to "contaminating" CoA, we found that Kir6.2/SUR2A channels were insensitive to 5-HD-CoA. In intact myocytes, 5-HD failed to reverse sarcK(ATP) channel activation by either metabolic inhibition or rilmakalim. GENERAL SIGNIFICANCE SarcK(ATP) channels are inhibited by 5-HD (provided that ATP is present) and CoA but insensitive to 5-HD-CoA. 5-HD is equally potent at "directly" inhibiting sarcK(ATP) and mitoK(ATP) channels. However, in intact cells, 5-HD fails to inhibit sarcK(ATP) channels, suggesting that mitochondria are the preconditioning-relevant targets of 5-HD.

更新日期：2019-11-01

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