A-kinase anchoring protein targeting of protein kinase A and regulation of HERG channels.
A-kinase anchoring protein targeting of protein kinase A and regulation of HERG channels.
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DOI：
10.1007/s00232-008-9118-4
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发表时间：
2008-05
影响因子：
2.4
通讯作者：
McDonald, Thomas V.
中科院分区：
文献类型：
--
作者：
Li, Yan;Sroubek, Jakub;Krishnan, Yamini;McDonald, Thomas V.
心脏的肾上腺素能刺激在心肌细胞中启动信号级联，增加cAMP的浓度。尽管cAMP升高可能发生在靶器官细胞的大面积区域，但由于其主要效应物蛋白激酶a （PKA）通过a激酶锚定蛋白（AKAPs）的局部浓度，其作用通常受到更多限制。HERG钾通道产生心脏快速激活延迟整流K+电流（I Kr），是cAMP/PKA调控的靶点。PKA对电流的调节可能在导致心律失常的遗传和获得性通道异常的发病机制中发挥作用。我们研究了akap介导的HERG通道调节的可能作用。在这里，我们报道了PKA-RII特异性AKAP抑制肽AKAP- is干扰PKA-RII的分布，并减少了pka依赖性HERG蛋白的磷酸化。AKAP-IS的功能后果是逆转camp依赖的HERG通道活性调节。为了进一步支持akap介导的激酶靶向HERG，在HEK细胞中表达的HERG共沉淀了PKA活性。溶解后的猪心膜蛋白的速度梯度离心分析表明，多个PKA-RI和PKA-RII结合蛋白与ERG通道共同沉积。然而，在异源共转染研究中，HERG与几种已知心脏表达的特异性akap存在物理关联。这些结果表明，一个或多个AKAP(s)将PKA靶向到HERG通道，并可能参与cAMP对I Kr的急性调节。本文的在线版本（doi:10.1007/s00232-008-9118-4）包含补充资料，仅供授权用户使用。
Adrenergic stimulation of the heart initiates a signaling cascade in cardiac myocytes that increases the concentration of cAMP. Although cAMP elevation may occur over a large area of a target-organ cell, its effects are often more restricted due to local concentration of its main effector, protein kinase A (PKA), through A-kinase anchoring proteins (AKAPs). The HERG potassium channel, which produces the cardiac rapidly activating delayed rectifying K+ current (I Kr), is a target for cAMP/PKA regulation. PKA regulation of the current may play a role in the pathogenesis of hereditary and acquired abnormalities of the channel leading to cardiac arrhythmia. We examined the possible role for AKAP-mediated regulation of HERG channels. Here, we report that the PKA-RII-specific AKAP inhibitory peptide AKAP-IS perturbs the distribution of PKA-RII and diminishes the PKA-dependent phosphorylation of HERG protein. The functional consequence of AKAP-IS is a reversal of cAMP-dependent regulation of HERG channel activity. In further support of AKAP-mediated targeting of kinase to HERG, PKA activity was coprecipitated from HERG expressed in HEK cells. Velocity gradient centrifugation of solubilized porcine cardiac membrane proteins showed that several PKA-RI and PKA-RII binding proteins cosediment with ERG channels. A physical association of HERG with several specific AKAPs with known cardiac expression, however, was not demonstrable in heterologous cotransfection studies. These results suggest that one or more AKAP(s) targets PKA to HERG channels and may contribute to the acute regulation of I Kr by cAMP. The online version of this article (doi:10.1007/s00232-008-9118-4) contains supplementary material, which is available to authorized users.
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