title: Carvedilol blocks cardiac KATP and KG but not IK1 channels by acting at the bundle-crossing regions.
abstract: We examined the effects of carvedilol on cardiac inwardly rectifying K(+) (Kir) channels, i.e., ATP-sensitive (K(ATP)), G-protein-activated (K(G)) and background (I(K1)) Kir channels. We found that carvedilol effectively inhibits K(ATP) and K(G), but not I(K1) channels. Carvedilol inhibits K(ATP) channels reconstituted in HEK293 cells with Kir6.2 lacking the C-terminal 26 amino acids (Kir6.2DeltaC26), suggesting that carvedilol acts in the channel pore. A sequence comparison of the three channels revealed that a cysteine residue, C166, in the inner helix of Kir6.2 is conserved in both Kir6.xs (K(ATP)) and Kir3.xs (K(G)), but not in Kir2.xs (I(K1)). The mutation of this residue (C166A) made Kir6.2DeltaC26 resistant to the drug. Homology modeling and docking simulation suggested that interaction between carvedilol and the pore could be located at the cytosolic portion of the inner helix (bundle-crossing region) containing C166. This study shows that carvedilol blocks specific groups of Kir channels by interacting with the bundle-crossing region.
authors.affiliation: Department of Pharmacology, Osaka University of Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kikuta
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kishimoto
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002460:Cell Line; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D002227:Carbazoles; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024683:Potassium Channels, Tandem Pore Domain; D011412:Propanolamines; D000077261:Carvedilol