Differential response of K(ATP) channels containing SUR2A or SUR2B subunits to nucleotides and pinacidil.
Differential response of K(ATP) channels containing SUR2A or SUR2B subunits to nucleotides and pinacidil.
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DOI：
10.1124/mol.58.6.1318
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发表时间：
2000-12
影响因子：
3.6
通讯作者：
F. Reimann;F. Gribble;F. M. Ashcroft
中科院分区：
文献类型：
--
作者：
F. Reimann;F. Gribble;F. M. Ashcroft
ATP敏感性K通道（K（ATP）通道）是K（ATP）通道开放剂（KCO）的靶点，如吡那地尔和P1075。这些通道由成孔Kir6.2和调节性磺酰脲受体（心脏和骨骼肌中的SUR 2A;平滑肌中的SUR 2B）形成。SUR 2的两种同种型仅在其最后42个氨基酸上不同，该区域既不包括步行者A和B核苷酸结合基序，也不包括所提出的KCO结合位点，但含有SUR 2 A或SUR 2 B的通道对核苷酸和KCO的反应不同。我们通过在非洲爪蟾卵母细胞中表达Kir6.2/SUR 2A和Kir6.2/SUR 2B电流来探索这种差异的基础。Kir6.2/SUR 2B而不是Kir6.2/SUR 2A电流被镁-核苷三磷酸MgATP和MgGTP激活，而两种通道类型都对二磷酸MgADP和MgGDP有反应。MgATP对Kir6.2/SUR 2B电流的激活解释了在Mg（2+）存在下ATP浓度-反应曲线如何向右移动。在没有核苷酸的情况下，吡那地尔和P1075激活Kir6.2/SUR 2B和Kir6.2/SUR 2A电流，但核苷酸的存在减慢了药物的解离速率。在MgATP存在下，SUR 2B对吡那地尔的反应逆转比SUR 2A慢约14倍。ATP的EC（50），通过其减缓吡那地尔解离速率的能力来测量，对于含有SUR 2A的通道也比SUR 2B高约20倍。我们的研究结果表明，核苷酸结合和/或水解增强SUR 2B相比，SUR 2A，更大的KCO-亲和力的SUR 2B相比，SUR 2A可能是这种改变的核苷酸处理的结果。
ATP-sensitive K-channels (K(ATP) channels) are the target for K(ATP)-channel openers (KCOs), such as pinacidil and P1075. These channels are formed from pore-forming Kir6.2 and regulatory sulfonylurea receptors (SUR2A in heart and skeletal muscle; SUR2B in smooth muscle). The two isoforms of SUR2 differ only in their final 42 amino acids, a region that includes neither the Walker A and B nucleotide binding motifs nor the proposed KCO binding site, yet channels containing SUR2A or SUR2B respond differently to both nucleotides and KCOs. We explored the basis for this difference by expressing Kir6.2/SUR2A and Kir6.2/SUR2B currents in Xenopus laevis oocytes. Kir6.2/SUR2B but not Kir6.2/SUR2A currents were activated by the Mg-nucleoside triphosphates MgATP and MgGTP, whereas both channel types responded to the diphosphates MgADP and MgGDP. This activation of Kir6.2/SUR2B currents by MgATP explains how the ATP concentration-response curve is shifted to the right in the presence of Mg(2+). In the absence of nucleotide, pinacidil and P1075 activated Kir6.2/SUR2B and Kir6.2/SUR2A currents, but the presence of nucleotide slowed the drug off-rates. In the presence of MgATP, the response to pinacidil reversed approximately 14 times more slowly with SUR2B than SUR2A. The EC(50) for ATP, measured by its ability to slow the pinacidil off-rate, was also approximately 20 times higher for channels containing SUR2A than SUR2B. Our findings suggest that nucleotide binding and/or hydrolysis is enhanced in SUR2B compared with SUR2A, and that the greater KCO-affinities of SUR2B compared with SUR2A may be a consequence of this altered nucleotide handling.