Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels.
Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels.
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DOI：
10.1016/j.bbamem.2019.183091
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发表时间：
2020-01
期刊：
影响因子：
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通讯作者：
E. Petersen;Mahmud Arif Pavel;Hao Wang;S. Hansen
中科院分区：
文献类型：
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作者：
E. Petersen;Mahmud Arif Pavel;Hao Wang;S. Hansen
与TWIK相关的K+通道（TREK-1）是一种机械和麻醉敏感通道，激活后可减轻疼痛并引起麻醉。最近，磷脂酶D2 （PLD2）被证明与通道结合并产生局部高浓度的磷脂酸（PA），这是一种阴离子信号脂质，可调控TREK-1。在生物膜中，细胞利用脂质异质性（脂质隔室）通过棕榈酸介导的PLD2定位来控制TREK-1的门控。在这里，我们讨论了机械力和麻醉剂破坏棕榈酸介导的PLD2定位的能力，从而导致TREK-1的机械和麻醉敏感特性。根据生物学背景下兴奋性和抑制性机制效应物和麻醉敏感离子通道的假设模型，讨论了这种间接基于脂质激活机制的可能后果。最后，我们讨论了局部产生的PA在TREK-1附近达到mM浓度的能力以及局部信号传导的生物物理学。棕榈酸介导的PLD2定位是TREK-1响应机械力和麻醉作用的中心控制机制。这篇文章是题为《膜和膜蛋白的分子生物物理学》特刊的一部分。
TWIK related K+ channel (TREK-1) is a mechano- and anesthetic sensitive channel that when activated attenuates pain and causes anesthesia. Recently the enzyme phospholipase D2 (PLD2) was shown to bind to the channel and generate a local high concentration of phosphatidic acid (PA), an anionic signaling lipid that gates TREK-1. In a biological membrane, the cell harnesses lipid heterogeneity (lipid compartments) to control gating of TREK-1 using palmitate-mediated localization of PLD2. Here we discuss the ability of mechanical force and anesthetics to disrupt palmitate-mediated localization of PLD2 giving rise to TREK-1's mechano- and anesthetic-sensitive properties. The likely consequences of this indirect lipid-based mechanism of activation are discussed in terms of a putative model for excitatory and inhibitory mechano-effectors and anesthetic sensitive ion channels in a biological context. Lastly, we discuss the ability of locally generated PA to reach mM concentrations near TREK-1 and the biophysics of localized signaling. Palmitate-mediated localization of PLD2 emerges as a central control mechanism of TREK-1 responding to mechanical force and anesthetic action. This article is part of a Special Issue entitled: Molecular biophysics of membranes and membrane proteins.