title: Characterization of KCNQ1 atrial fibrillation mutations reveals distinct dependence on KCNE1.
abstract: The I(Ks) potassium channel, critical to control of heart electrical activity, requires assembly of α (KCNQ1) and β (KCNE1) subunits. Inherited mutations in either I(Ks) channel subunit are associated with cardiac arrhythmia syndromes. Two mutations (S140G and V141M) that cause familial atrial fibrillation (AF) are located on adjacent residues in the first membrane-spanning domain of KCNQ1, S1. These mutations impair the deactivation process, causing channels to appear constitutively open. Previous studies suggest that both mutant phenotypes require the presence of KCNE1. Here we found that despite the proximity of these two mutations in the primary protein structure, they display different functional dependence in the presence of KCNE1. In the absence of KCNE1, the S140G mutation, but not V141M, confers a pronounced slowing of channel deactivation and a hyperpolarizing shift in voltage-dependent activation. When coexpressed with KCNE1, both mutants deactivate significantly slower than wild-type KCNQ1/KCNE1 channels. The differential dependence on KCNE1 can be correlated with the physical proximity between these positions and KCNE1 as shown by disulfide cross-linking studies: V141C forms disulfide bonds with cysteine-substituted KCNE1 residues, whereas S140C does not. These results further our understanding of the structural relationship between KCNE1 and KCNQ1 subunits in the I(Ks) channel, and provide mechanisms for understanding the effects on channel deactivation underlying these two atrial fibrillation mutations.
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Priscilla J
authors.initials: PJ
authors.lastname: Chan
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Osteen
authors.forename: Dazhi
authors.initials: D
authors.lastname: Xiong
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bohnen
authors.forename: Darshan
authors.initials: D
authors.lastname: Doshi
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Sampson
authors.forename: Steven O
authors.initials: SO
authors.lastname: Marx
authors.forename: Arthur
authors.initials: A
authors.lastname: Karlin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D003545:Cysteine