力快速转化为生物信号使活细胞能够响应其环境中的机械力。该力被认为最初影响质膜,然后改变膜蛋白的行为。磷脂酶D2(PLD2)是一种机械敏感性酶,由胆固醇和饱和神经节苷脂(GM1)组成的结构化膜-脂质位点调节。在这里,我们显示TWIK相关的K通道(TREK-1)的拉伸激活是由PLD2和涉及哺乳动物细胞中有序GM1和4,5-二磷酸(PIP2)簇的空间模式机械诱发的。首先,机械力使有序的脂质变形,它破坏了PLD2与GM1脂质的相互作用,并允许TREK-1和PLD2的复合物与PIP2簇结合。与PIP2的结合激活了酶,产生第二信使磷脂酸(PA)的通道。催化非活性PLD2的共表达抑制生物膜中的TREK-1拉伸电流。胆固醇的细胞摄取抑制培养物中的TREK-1电流,星形胶质细胞中胆固醇的消耗从小鼠脑中的GM1脂质释放TREK-1。果蝇中PLD2直系同源物的耗尽导致对机械力的超敏反应。我们得出的结论是,PLD2机械敏感性与TREK-1离子渗透性结合会引起机械诱发反应。
“哎呀!”:你刚刚在咖啡桌的尖角上刺伤了你的小脚趾。这种痛苦的感觉源于神经细胞将有关外力的信息转化为大脑可以解释的电信号。越来越多,新的证据表明,这一过程可能始于这些细胞膜内的脂肪结构。细胞膜是由两个相互连接的,其中嵌入结构或分子自由移动的柔性脂质薄片。这种组织允许膜对外力做出物理响应,反过来,设置分子事件的运动链,帮助微调细胞如何将这些信息传递到大脑。例如,一种被称为PLD2的酶与脂筏结合-精确排列,膜中的刚性脂肪“团块”,部分由胆固醇形成。PLD2还被证明与离子通道TREK-1物理相互作用,然后激活离子通道TREK-1,这是一种基于膜的蛋白质,有助于防止神经细胞传递疼痛信号。然而,由于所涉及分子的性质和大小,难以研究这些相互作用的确切机制。为了解决这个问题,彼得森等人。将一种称为超分辨率成像的技术与一种新方法相结合,使他们能够观察膜脂对压力和流体剪切的反应。实验表明,机械力破坏了脂筏的精心排列,导致PLD2和TREK-1释放。然后,它们可以穿过周围的膜,到达打开TREK-1的开关。进一步的工作表明,小鼠细胞的胆固醇水平直接影响了团块如何形成和与PLD2结合,上下拨TREK-1介导的保护信号。总的来说,Petersen等人的研究。显示神经细胞膜可以包含基于胆固醇的“脂肪传感器”,有助于检测外力并参与疼痛调节。通过解剖这些过程,有可能更好地了解和治疗糖尿病和狼疮等疾病,这与疼痛敏感性和组织中胆固醇水平升高有关。
Rapid conversion of force into a biological signal enables living cells to respond to mechanical forces in their environment. The force is believed to initially affect the plasma membrane and then alter the behavior of membrane proteins. Phospholipase D2 (PLD2) is a mechanosensitive enzyme that is regulated by a structured membrane-lipid site comprised of cholesterol and saturated ganglioside (GM1). Here we show stretch activation of TWIK-related K+ channel (TREK-1) is mechanically evoked by PLD2 and spatial patterning involving ordered GM1 and 4,5-bisphosphate (PIP2) clusters in mammalian cells. First, mechanical force deforms the ordered lipids, which disrupts the interaction of PLD2 with the GM1 lipids and allows a complex of TREK-1 and PLD2 to associate with PIP2 clusters. The association with PIP2 activates the enzyme, which produces the second messenger phosphatidic acid (PA) that gates the channel. Co-expression of catalytically inactive PLD2 inhibits TREK-1 stretch currents in a biological membrane. Cellular uptake of cholesterol inhibits TREK-1 currents in culture and depletion of cholesterol from astrocytes releases TREK-1 from GM1 lipids in mouse brain. Depletion of the PLD2 ortholog in flies results in hypersensitivity to mechanical force. We conclude PLD2 mechanosensitivity combines with TREK-1 ion permeability to elicit a mechanically evoked response.
“Ouch!”: you have just stabbed your little toe on the sharp corner of a coffee table. That painful sensation stems from nerve cells converting information about external forces into electric signals the brain can interpret. Increasingly, new evidence is suggesting that this process may be starting at fat-based structures within the membrane of these cells. The cell membrane is formed of two interconnected, flexible sheets of lipids in which embedded structures or molecules are free to move. This organisation allows the membrane to physically respond to external forces and, in turn, to set in motion chains of molecular events that help fine-tune how cells relay such information to the brain. For instance, an enzyme known as PLD2 is bound to lipid rafts – precisely arranged, rigid fatty ‘clumps’ in the membrane that are partly formed of cholesterol. PLD2 has also been shown to physically interact with and then activate the ion channel TREK-1, a membrane-based protein that helps to prevent nerve cells from relaying pain signals. However, the exact mechanism underpinning these interactions is difficult to study due to the nature and size of the molecules involved. To address this question, Petersen et al. combined a technology called super-resolution imaging with a new approach that allowed them to observe how membrane lipids respond to pressure and fluid shear. The experiments showed that mechanical forces disrupt the careful arrangement of lipid rafts, causing PLD2 and TREK-1 to be released. They can then move through the surrounding membrane where they reach a switch that turns on TREK-1. Further work revealed that the levels of cholesterol available to mouse cells directly influenced how the clumps could form and bind to PLD2, and in turn, dialled up and down the protective signal mediated by TREK-1. Overall, the study by Petersen et al. shows that the membrane of nerve cells can contain cholesterol-based ‘fat sensors’ that help to detect external forces and participate in pain regulation. By dissecting these processes, it may be possible to better understand and treat conditions such as diabetes and lupus, which are associated with both pain sensitivity and elevated levels of cholesterol in tissues.