title: S641 contributes HERG K+ channel inactivation.
abstract: The kinetics of voltage-dependent inactivation of the rapidly activating delayed rectifier, IKr, are unique among K+ channels. The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr and shares a high degree of homology with ether-a-gogo (EAG) channels that do not inactivate. Within those segments thought to contribute to the channel pore, HERG possesses several serine residues that are not present in EAG channels. Two of these serines, S620 and S631, are known to be required for inactivation. We now show that a third serine, S641, which resides in the outer portion of the sixth transmembrane segment, is also critical for normal inactivation. As with the other serines, S641 is also involved in maintaining ion selectivity of the HERG channel and alters sensitivity to block by E4031. Larger charged or polar substitutions (S641D and S641T) disrupted C-type inactivation in HERG. Smaller aliphatic and more conservative substitutions (S641A and S641C) facilitated C-type inactivation. Our data show that, like S620 and S631, S641 is another key residue for the rapid inactivation. The altered inactivation of mutations at S620, S631, and S641 were dominant, suggesting that a network of hydroxyl side chains is required for the unique inactivation, permeation, and rectification of HERG channels.
authors.affiliation: Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Bian
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.forename: Yonathan
authors.initials: Y
authors.lastname: Melman
authors.forename: Thomas V
authors.initials: TV
authors.lastname: McDonald
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001703:Biophysics / Q000379:methods; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008133:Long QT Syndrome / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D012694:Serine