Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue.
The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I(Ks) channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of beta-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with beta-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between beta-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
Saucerman
Jeffrey J
JJ
Department of Bioengineering, Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla92037-0412, USA.
Healy
Sarah N
SN
Belik
Mary E
ME
Puglisi
Jose L
JL
McCulloch
Andrew D
AD
D000200:Action Potentials / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D058665:Adrenergic beta-1 Receptor Agonists; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004562:Electrocardiography; D006352:Heart Ventricles / Q000166:cytology; D017136:Ion Transport / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008955:Models, Cardiovascular; D008958:Models, Molecular; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017354:Point Mutation; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011817:Rabbits; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D013329:Structure-Activity Relationship
D048868:Adaptor Proteins, Signal Transducing; D058665:Adrenergic beta-1 Receptor Agonists; D003598:Cytoskeletal Proteins; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D018342:Receptors, Adrenergic, beta-1; D007545:Isoproterenol; D011188:Potassium