Phosphatidylinositol-4,5-bisphosphate (PIP(2)) stabilizes the open pore conformation of the Kv11.1 (hERG) channel.
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.
Rodriguez
Nicolas
N
Institut National de la Santé et de la Recherche Médicale, Nantes, France.
Amarouch
Mohamed Yassine
MY
Montnach
Jérôme
J
Piron
Julien
J
Labro
Alain J
AJ
Charpentier
Flavien
F
Mérot
Jean
J
Baró
Isabelle
I
Loussouarn
Gildas
G
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
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