title: Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit.
abstract: Kir3.4 and Kir3.1 potassium channel subunits mediate the acetylcholine induced inwardly rectifying current I(KACh) in the heart. We found a glycine to arginine substitution in codon 247 of Kir3.4 in a patient with a single episode of atrial fibrillation (AF). Expression in Xenopus laevis oocytes and two-electrode voltage-clamp revealed that Kir3.4-G247R basal current was reduced compared to wild-type Kir3.4 and co-expression with the muscarinic acetylcholine receptor type 2 showed that also the acetylcholine induced current was severely reduced in Kir3.4-G247R, indicating that the mutation interfered with activation by the stimulatory G betagamma-subunits. Co-expression of Kir3.4-G247R with wild-type Kir3.4 or Kir3.1 had a compensating effect on both basal current levels and the response to muscarinic stimulation suggesting the function of Kir3.4-G247R is compensated in vivo. This may explain the lack of clear clinical manifestations and further studies are necessary to elucidate if mutations in Kir3.4 are predisposing AF.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, 12.5.10, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Kirstinec@mfi.ku.dk
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.forename: Lasse Steen
authors.initials: LS
authors.lastname: Ravn
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.forename: Jin Liang
authors.initials: JL
authors.lastname: Sui
authors.forename: Morten
authors.initials: M
authors.lastname: Duno
authors.forename: Stig
authors.initials: S
authors.lastname: Haunso
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Jesper Hastrup
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Soren-Peter
authors.initials: SP
authors.lastname: Olesen
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484274:KCNJ5 protein, human; D011188:Potassium