Regulation of the ATP-sensitive Potassium Channel Subunit, Kir6.2, by a Ca2+-dependent Protein Kinase C
Regulation of the ATP-sensitive Potassium Channel Subunit, Kir6.2, by a Ca2+-dependent Protein Kinase C
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DOI：
10.1074/jbc.m111.243923
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发表时间：
2012-02-24
影响因子：
4.8
通讯作者：
Tinker, Andrew
中科院分区：
文献类型：
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作者：
Aziz, Qadeer;Thomas, Alison M.;Tinker, Andrew
ATP敏感钾（K-ATP）通道的活性受细胞内ATP和ADP的浓度控制，因此对细胞的代谢状态作出反应。蛋白激酶A （PKA）或蛋白激酶C （PKC）磷酸化KATP通道导致通道活性的调节，在调节平滑肌张力中尤为重要。在分子水平上，平滑肌通道由磺酰脲亚基（SUR2B）和成孔亚基Kir6.1和/或Kir6.2组成。此前，Kir6.1/SUR2B通道被PKC抑制，Kir6.2/SUR2B通道被激活或对PKC无反应。在这项研究中，我们研究了由内向整流亚基Kir6.2和磺酰脲亚基SUR2B形成的通道复合物的调制。利用生物化学和电生理技术的结合，我们表明这种复合物可以被蛋白激酶C以Ca2+依赖的方式抑制，这种抑制可能是内化的结果。我们在Kir6.2的远端C端发现了一个残基（Ser-372），其磷酸化导致通道复合物的下调。这种抑制作用与激活不同，激活是在低水平的通道活性下看到的。
The activity of ATP-sensitive potassium (K-ATP) channels is governed by the concentration of intracellular ATP and ADP and is thus responsive to the metabolic status of the cell. Phosphorylation of KATP channels by protein kinase A (PKA) or protein kinase C (PKC) results in the modulation of channel activity and is particularly important in regulating smooth muscle tone. At the molecular level the smooth muscle channel is composed of a sulfonylurea subunit (SUR2B) and a pore-forming subunit Kir6.1 and/or Kir6.2. Previously, Kir6.1/SUR2B channels have been shown to be inhibited by PKC, and Kir6.2/SUR2B channels have been shown to be activated or have no response to PKC. In this study we have examined the modulation of channel complexes formed of the inward rectifier subunit, Kir6.2, and the sulfonylurea subunit, SUR2B. Using a combination of biochemical and electrophysiological techniques we show that this complex can be inhibited by protein kinase C in a Ca2+-dependent manner and that this inhibition is likely to be as a result of internalization. We identify a residue in the distal C terminus of Kir6.2 (Ser-372) whose phosphorylation leads to down-regulation of the channel complex. This inhibitory effect is distinct from activation which is seen with low levels of channel activity.