Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid
Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid
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DOI：
10.1073/pnas.1407160111
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发表时间：
2014-09-16
影响因子：
11.1
通讯作者：
Sandoz, Guillaume
中科院分区：
文献类型：
--
作者：
Comoglio, Yannick;Levitz, Joshua;Sandoz, Guillaume
膜脂作为蛋白质的第二信使和对接部位，在细胞信号转导中发挥核心作用。关于脂类信号的一个主要问题是，可扩散的脂类是否可以选择性地针对特定的蛋白质。脂调节的膜蛋白家族之一是TWIK相关K通道(TREK)亚家族的K2P通道：TREK1、TREK2和TWK相关的花生四烯酸刺激的K+通道(TRAAK)。我们研究了磷脂酶D(PLD)通过磷脂酰胆碱水解产生的磷脂酸(PA)对Trek通道的调节作用。尽管这三个通道都对PA敏感，但我们发现只有TREK1和TREK2被PLD2增强，这些通道都没有被PLD1调制，这表明了令人惊讶的选择性。我们发现PLD2与TREK1和TREK2的C末端直接结合，而不与TRAAK结合。这一结果导致了一个通过将磷脂酶定位到特定的效应蛋白来选择性调节血脂的模型。最后，我们发现PLD2对Trek通道的调节发生在海马神经元中。
Membrane lipids serve as second messengers and docking sites for proteins and play central roles in cell signaling. A major question about lipid signaling is whether diffusible lipids can selectively target specific proteins. One family of lipid-regulated membrane proteins is the TWIK-related K channel (TREK) subfamily of K2P channels: TREK1, TREK2, and TWIK-related arachdonic acid stimulated K+ channel (TRAAK). We investigated the regulation of TREK channels by phosphatidic acid (PA), which is generated by phospholipase D (PLD) via hydrolysis of phosphatidylcholine. Even though all three of the channels are sensitive to PA, we found that only TREK1 and TREK2 are potentiated by PLD2 and that none of these channels is modulated by PLD1, indicating surprising selectivity. We found that PLD2, but not PLD1, directly binds to the C terminus of TREK1 and TREK2, but not to TRAAK. The results have led to a model for selective lipid regulation by localization of phospholipid enzymes to specific effector proteins. Finally, we show that regulation of TREK channels by PLD2 occurs natively in hippocampal neurons.