Membrane pools of phosphatidylinositol-4-phosphate regulate KCNQ1/KCNE1 membrane expression.
Membrane pools of phosphatidylinositol-4-phosphate regulate KCNQ1/KCNE1 membrane expression.
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DOI：
10.1038/s42003-021-02909-1
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发表时间：
2021-12-14
影响因子：
5.9
通讯作者：
Lopes CMB
中科院分区：
文献类型：
--
作者：
Braun C;Parks XX;Qudsi H;Lopes CMB
质膜磷脂酰肌醇4-磷酸(PI4P)是PI(4，5)P2的前体，PI(4，5)P2是大量离子通道的重要调节因子。尽管磷脂PI(4，5)P2在稳定离子通道功能中的作用已被证实，但对于磷脂在通道膜定位中的作用，特别是PI4P在通道功能和定位中的作用，我们知之甚少。磷脂酰肌醇4-激酶(PI4Ks)合成PI4P。我们的数据表明，抑制PI4K和持续降低质膜PI4P水平会导致KCNQ1/KCNE1通道膜定位和功能的降低。此外，我们发现与长QT综合征相关的突变会影响与磷脂的通道相互作用，从而导致膜表达的减少。我们表明，LQT1相关的C末端缺失突变体的表达消除了PI4Kinase介导的膜表达的减少，并挽救了磷脂靶向突变的膜表达。我们的结果表明，PI4P在离子通道调节中发挥了新的作用。我们的数据表明，由于抑制PI4K或由于突变的结果，膜上PI4P对通道的可用性降低，显著抑制了KCNQ1/KCNE1通道膜的定位和电流。我们的结果可能对其他PI4P结合通道的调控有一定的意义。布劳恩等人。研究PI4-激酶及其脂类产物PI4P在KCNQ通道功能和亚细胞定位中的作用。这些结果提示PI4K抑制可能对心脏电生理产生有害影响，并提示该通道的远端C-末端在PI4P调节KCNQ1/KCNE1通道中起关键作用。
Plasma membrane phosphatidylinositol 4-phosphate (PI4P) is a precursor of PI(4,5)P2, an important regulator of a large number of ion channels. Although the role of the phospholipid PI(4,5)P2 in stabilizing ion channel function is well established, little is known about the role of phospholipids in channel membrane localization and specifically the role of PI4P in channel function and localization. The phosphatidylinositol 4-kinases (PI4Ks) synthesize PI4P. Our data show that inhibition of PI4K and prolonged decrease of levels of plasma membrane PI4P lead to a decrease in the KCNQ1/KCNE1 channel membrane localization and function. In addition, we show that mutations linked to Long QT syndrome that affect channel interactions with phospholipids lead to a decrease in membrane expression. We show that expression of a LQT1-associated C-terminal deletion mutant abolishes PI4Kinase-mediated decrease in membrane expression and rescues membrane expression for phospholipid-targeting mutations. Our results indicate a novel role for PI4P on ion channel regulation. Our data suggest that decreased membrane PI4P availability to the channel, either due to inhibition of PI4K or as consequence of mutations, dramatically inhibits KCNQ1/KCNE1 channel membrane localization and current. Our results may have implications to regulation of other PI4P binding channels. Braun et al. investigate the effects of PI 4-kinases and their lipid product, PI4P, in KCNQ channel function and sub-cellular localization. These results suggest a possible harmful effect of PI4K inhibition on cardiac electrophysiology and suggest the distal C-terminus of the channel is critical for PI4P regulation of the KCNQ1/KCNE1 channel.
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DOI：
10.1042/bj20090428
发表时间：
2009-07-29
期刊：
The Biochemical journal
影响因子：
--
作者：
Hammond GR;Schiavo G;Irvine RF
通讯作者：
Irvine RF
影响因子：
--
作者：
Minogue, Shane;Waugh, Mark G
通讯作者：
Waugh, Mark G
影响因子：
7.7
作者：
Nash, Craig A.;Wei, Wenhui;Smrcka, Alan V.
通讯作者：
Smrcka, Alan V.
影响因子：
5
作者：
Moreno, Cristina;Oliveras, Anna;Valenzuela, Carmen
通讯作者：
Valenzuela, Carmen
影响因子：
5.6
作者：
Choveau FS;Abderemane-Ali F;Coyan FC;Es-Salah-Lamoureux Z;Baró I;Loussouarn G
通讯作者：
Loussouarn G