title: Hypoxia inhibits maturation and trafficking of hERG K(+) channel protein: Role of Hsp90 and ROS.
abstract: We previously reported that reactive oxygen species (ROS) generated during hypoxia decrease hERG current density and protein expression in HEK cells stably expressing hERG protein. In the present study, we investigated the molecular mechanisms involved in hypoxia-induced downregulation of hERG protein. Culturing cells at low temperatures and addition of chemical chaperones during hypoxia restored hERG expression and currents to normoxic levels while antiarrhythmic drugs, which selectively block hERG channels, had no effect on hERG protein levels. Pulse chase studies showed that hypoxia blocks maturation of the core glycosylated form in the endoplasmic reticulum (ER) to the fully glycosylated form on the cell surface. Co-immunoprecipitation experiments revealed that hypoxia inhibited interaction of hERG with Hsp90 chaperone required for maturation, which was restored in the presence of ROS scavengers. These results demonstrate that ROS generated during hypoxia prevents maturation of the hERG protein by inhibiting Hsp90 interaction resulting in decreased protein expression and currents.
authors: Center for Systems Biology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. jnanduri@uchicago.edu
authors: Jayasri
authors: J
authors: Nanduri
authors: Pamela
authors: P
authors: Bergson
authors: Ning
authors: N
authors: Wang
authors: Eckhard
authors: E
authors: Ficker
authors: Nanduri R
authors: NR
authors: Prabhakar
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018841:HSP90 Heat-Shock Proteins; D017382:Reactive Oxygen Species