title: The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking.
abstract: Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α, and genetic knockdown of Hsp90α, but not Hsp90β, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effects.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Eskew
authors.forename: George A
authors.initials: GA
authors.lastname: Vielhauer
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D003720:Densitometry; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008954:Models, Biological; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D018841:HSP90 Heat-Shock Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering