Kweon Hae-Jin, Yu Soo-Young, Kim Dong-Il, Suh Byung-Chang
Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.
PLoS One. 2015 Mar 17;10(3):e0122014. doi: 10.1371/journal.pone.0122014. eCollection 2015.
Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs) are typical proton sensors in the central nervous system (CNS) and the peripheral nervous system (PNS). In addition to ASICs, capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channels can also mediate proton-mediated pain signaling. In spite of their importance in perception of pH fluctuations, the regulatory mechanisms of these proton-sensitive ion channels still need to be further investigated. Here, we compared regulation of ASICs and TRPV1 by membrane phosphoinositides, which are general cofactors of many receptors and ion channels. We observed that ASICs do not require membrane phosphatidylinositol 4-phosphate (PI(4)P) or phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for their function. However, TRPV1 currents were inhibited by simultaneous breakdown of PI(4)P and PI(4,5)P2. By using a novel chimeric protein, CF-PTEN, that can specifically dephosphorylate at the D3 position of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), we also observed that neither ASICs nor TRPV1 activities were altered by depletion of PI(3,4,5)P3 in intact cells. Finally, we compared the effects of arachidonic acid (AA) on two proton-sensitive ion channels. We observed that AA potentiates the currents of both ASICs and TRPV1, but that they have different recovery aspects. In conclusion, ASICs and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4)P, PI(4,5)P2, and AA, although they have common roles as proton sensors. Further investigation about the complementary roles and respective contributions of ASICs and TRPV1 in proton-mediated signaling is necessary.
在炎症、缺血性中风、感染和癌症等引发疼痛的病理状况下会释放质子。在正常的突触活动过程中，质子被认为在神经传递过程中发挥作用。酸敏感离子通道（ASICs）是中枢神经系统（CNS）和外周神经系统（PNS）中的典型质子传感器。除了ASICs，辣椒素和热激活的瞬时受体电位香草酸受体1（TRPV1）通道也可介导质子介导的疼痛信号传导。尽管它们在感知pH波动方面很重要，但这些质子敏感离子通道的调节机制仍需进一步研究。在此，我们比较了膜磷酸肌醇对ASICs和TRPV1的调节作用，膜磷酸肌醇是许多受体和离子通道的常见辅助因子。我们观察到，ASICs的功能不需要膜磷脂酰肌醇4-磷酸（PI(4)P）或磷脂酰肌醇4,5-二磷酸（PI(4,5)P2）。然而，PI(4)P和PI(4,5)P2的同时分解会抑制TRPV1电流。通过使用一种新型嵌合蛋白CF-PTEN，其可特异性地使磷脂酰肌醇3,4,5-三磷酸（PI(3,4,5)P3）的D3位置去磷酸化，我们还观察到在完整细胞中，PI(3,4,5)P3的耗尽不会改变ASICs和TRPV1的活性。最后，我们比较了花生四烯酸（AA）对两种质子敏感离子通道的影响。我们观察到AA增强了ASICs和TRPV1的电流，但它们具有不同的恢复情况。总之，尽管ASICs和TRPV1作为质子传感器具有共同作用，但它们对膜磷脂如PI(4)P、PI(4,5)P2和AA具有不同的敏感性。有必要进一步研究ASICs和TRPV1在质子介导信号传导中的互补作用和各自贡献。
