title: Phosphatidylinositol4-phosphate 5-kinase prevents the decrease in the HERG potassium current induced by Gq protein-coupled receptor stimulation.
abstract: The human ether-a-go-go-related gene (HERG) potassium current (IHERG) has been shown to decrease in amplitude following stimulation with Gq protein-coupled receptors (GqRs), such as α1-adrenergic and M1-muscarinic receptors (α1R and M1R, respectively), at least partly via the reduction of membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The present study was designed to investigate the modulation of HERG channels by PI(4,5)P2 and phosphatidylinositol4-phosphate 5-kinase (PI(4)P5-K), a synthetic enzyme of PI(4,5)P2. Whole-cell patch-clamp recordings were used to examine the activity of HERG channels expressed heterologously in Chinese Hamster Ovary cells. The stimulation of α1R with phenylephrine or M1R with acetylcholine decreased the amplitude of IHERG accompanied by a significant acceleration of deactivation kinetics and the effects on IHERG were significantly attenuated in cells expressing PI(4)P5-K. The density of IHERG in cells expressing GqRs alone was significantly increased by the coexpression of PI(4)P5-K without significant differences in the voltage dependence of activation and deactivation kinetics. The kinase-deficient substitution mutant, PI(4)P5-K-K138A did not have these counteracting effects on the change in IHERG by M1R stimulation. These results suggest that the current density of IHERG is closely dependent on the membrane PI(4,5)P2 level, which is regulated by PI(4)P5-K and GqRs and that replenishing PI(4,5)P2 by PI(4)P5-K recovers IHERG.
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan; Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd, Osaka 554-0022, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Kubo
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Omatsu-Kanbe
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Shiga 520-2192, Japan. Electronic address: matuurah@belle.shiga-med.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D010656:Phenylephrine / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D010656:Phenylephrine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000109:Acetylcholine
keywords: Arrhythmia; Gq protein-coupled receptors; HERG channel; PI(4)P5-K; PI(4,5)P(2)