title: A422T mutation in HERG potassium channel retained in ER is rescurable by pharmacologic or molecular chaperones.
abstract: In the present study, we characterized biologic and electrophysiologic consequences of A422T mutation in HERG K(+) channel and the role of pharmacologic or molecular chaperons by employing a heterogeneous expression system in HEK 293 cells. It was found that A422T mutation led to a marked decrease in whole-cell recording currents, and that a complexly glycosylated form protein band at 155 kDa was missing by Western blotting analysis compared to wild type (WT). And the mutant protein was mainly located in the cytoplasm as illustrated in immunocytochemical assay, indicating that the mutation underwent a trafficking defect. In addition, A422T mutation exerted remarkable dominant-negative suppression on WT, resulting in the alteration in the kinetic processes. Strikingly, trafficking-deficient A422T mutation was partially rescued by incubating the cells at a lower temperature, administration of pharmacologic chaperon, E4031 or overexpression of a chaperon molecule, Hsp90, but not Hsp70. In conclusion, missense A422T mutation in HERG K(+) channel results in its trafficking defect, which is rescurable by pharmacologic or molecular chaperones.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: XiangMei
authors.initials: X
authors.lastname: Zhang
authors.forename: ZhenSheng
authors.initials: Z
authors.lastname: Hu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhuang
authors.forename: ZhongHua
authors.initials: Z
authors.lastname: Zhu
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: ZhongZhong
authors.initials: Z
authors.lastname: Zhao
authors.forename: ChaoYing
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis; D003080:Cold Temperature; D000072237:ERG1 Potassium Channel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D020125:Mutation, Missense; D009570:Nitriles / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects
chemical_list: C120578:E 4010; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C000606913:KCNH2 protein, human; D018832:Molecular Chaperones; D009570:Nitriles; D010880:Piperidines