title: Phosphatidylinositol-4,5-bisphosphate (PIP(2)) stabilizes the open pore conformation of the Kv11.1 (hERG) channel.
abstract: Phosphatidylinositol-4,5-bisphosphate (PIP(2)) is a phospholipid that has been shown to modulate several ion channels, including some voltage-gated channels like Kv11.1 (hERG). From a biophysical perspective, the mechanisms underlying this regulation are not well characterized. From a physiological perspective, it is critical to establish whether the PIP(2) effect is within the physiological concentration range. Using the giant-patch configuration of the patch-clamp technique on COS-7 cells expressing hERG, we confirmed the activating effect of PIP(2). PIP(2) increased the hERG maximal current and concomitantly slowed deactivation. Regarding the molecular mechanism, these increased amplitude and slowed deactivation suggest that PIP(2) stabilizes the channel open state, as it does in KCNE1-KCNQ1. We used kinetic models of hERG to simulate the effects of the phosphoinositide. Simulations strengthened the hypothesis that PIP(2) is more likely stabilizing the channel open state than affecting the voltage sensors. From the physiological aspect, we established that the sensitivity of hERG to PIP(2) comes close to that of KCNE1-KCNQ1 channels, which lies in the range of physiological PIP(2) variations.
authors: Institut National de la Santé et de la Recherche Médicale, Nantes, France.
authors: Nicolas
authors: N
authors: Rodriguez
authors: Mohamed Yassine
authors: MY
authors: Amarouch
authors: Jérôme
authors: J
authors: Montnach
authors: Julien
authors: J
authors: Piron
authors: Alain J
authors: AJ
authors: Labro
authors: Flavien
authors: F
authors: Charpentier
authors: Jean
authors: J
authors: Mérot
authors: Isabelle
authors: I
authors: Baró
authors: Gildas
authors: G
authors: Loussouarn
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008954:Models, Biological; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology*; D011107:Polylysine / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D014162:Transfection
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D024642:Potassium Channels, Voltage-Gated; D011107:Polylysine; D008274:Magnesium