Human EAG channels are directly modulated by PIP_2 as revealed by electrophysiological and optical interference investigations
【摘要】：Voltage-gated ether à go-go(EAG) K~+ channels are expressed in various types of cancer cells and also in the central nervous system. Aberrant overactivation of human EAG1(h EAG1) channels is associated with cancer and neuronal disorders such as Zimmermann-Laband and Temple-Baraitser syndromes. Although h EAG1 channels are recognized as potential therapeutic targets, regulation of their functional properties is only poorly understood. Here, we show that the membrane lipid phosphatidylinositol 4,5-bisphosphate(PIP_2) is a potent inhibitory gating modifier of hE AG1 channels. PIP_2 inhibits the channel activity by directly binding to a short Nterminal segment of the channel important for Ca~(2+)/calmodulin(CaM) binding as evidenced by biolayer interferometry measurements. Conversely, depletion of endogenous PIP_2 either by serotonininduced phospholipase C(PLC) activation or by a rapamycin-induced translocation system enhances the channel activity at physiological membrane potentials, suggesting that PIP_2 exerts a tonic inhibitory influence. Our study, combining electrophysiological and direct binding assays, demonstrates that hE AG1 channels are subject to potent inhibitory modulation by multiple phospholipids and suggests that manipulations of the PIP_2 signaling pathway may represent a strategy to treat hE AG1 channel-associated diseases.
【作者单位】：Key Laboratory of Systems Biomedicine(Ministry of Education), Institute of Systems Biomedicine, Shanghai Jiao Tong University Center for Molecular Biomedicine, Department of Biophysics, Friedrich Schiller University Jena & Jena University Hospital Department of Physiology, University of Pennsylvania Key Laboratory of Systems Biomedicine(inistry of Education), Institute of Systems Biomedicine, Shanghai Jiao Tong University State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine,Shanghai Jiao Tong University 【分类号】：