title: Blockade of HERG K+ channel by an antihistamine drug brompheniramine requires the channel binding within the S6 residue Y652 and F656.
abstract: A number of clinically used drugs block delayed rectifier K+ channels and prolong the duration of cardiac action potentials associated with long QT syndrome. This study investigated the molecular mechanisms of voltage-dependent inhibition of human ether-a-go-go-related gene (HERG) delayed rectifier K+ channels expressed in HEK-293 cells by brompheniramine, an antihistamine. Brompheniramine inhibited HERG current in a concentration-dependent manner with the half-maximal inhibitory concentration (IC50) value of 1.7 microm at 0 mV. A block of HERG current by brompheniramine was enhanced by progressive membrane depolarization and showed significantly negative shift in voltage-dependence of channel activation. Inhibition of HERG current by brompheniramine showed time-dependence. The S6 residue HERG mutant Y652A and F656C largely reduced the blocking potency of HERG current. These results indicate that brompheniramine mainly inhibited the HERG potassium channel through the residue Y652 and F656 and these residues may be an obligatory determinant in inhibition of HERG current for brompheniramine.
authors.affiliation: Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 305-600, Korea.
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Park
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Kim
mesh_terms: D001977:Brompheniramine / Q000633:toxicity*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D006801:Humans; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism; D008564:Membrane Potentials; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010649:Phenylalanine / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000633:toxicity*; D021122:Protein Subunits; D018570:Risk Assessment; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D021122:Protein Subunits; D014443:Tyrosine; D010649:Phenylalanine; D001977:Brompheniramine