title: HERG channel trafficking.
abstract: Mutations in the cardiac potassium channel hERG/IKr cause inherited long QT syndrome with increased susceptibility to ventricular arrhythmias. Several mutations in hERG produce trafficking-deficient channels that are retained in the endoplasmic reticulum (ER). Surface expression of certain mutations (i.e. hERG G601S) can be restored by specific channel blockers. Although hERG currents have been studied extensively, little is known about proteins in the processing pathway. Using biochemical and electrophysiological assays we show that the cytosolic chaperones Hsp70 and Hsp90 interact transiently with wild-type hERG. Inhibition of Hsp90 prevents maturation and reduces hERG/IKr currents. Trafficking-deficient mutants remain tightly associated with chaperones in the ER until trafficking is restored, e.g. by channel blockers. hERG/chaperone complexes represent novel targets for therapeutic compounds with cardiac liability such as arsenic, which is used in the treatment of leukaemias. Arsenic interferes with the formation of hERG/chaperone complexes and inhibits hERG maturation causing ECG abnormalities. We conclude that Hsp9O and Hsp70 are crucial for productive folding of wild-type hERG. Therapeutic compounds that inhibit chaperone function produce a novel form of acquired long QT syndrome not by direct channel block but by reduced surface expression due to an acquired trafficking defect of hERG.
authors.affiliation: Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland OH 44109, USA.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Ficker
authors.forename: Adrienne
authors.initials: A
authors.lastname: Dennis
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kuryshev
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Wible
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Brown
mesh_terms: D000200:Action Potentials; D000818:Animals; D000072237:ERG1 Potassium Channel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D008133:Long QT Syndrome; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D021381:Protein Transport
chemical_list: 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; D024642:Potassium Channels, Voltage-Gated