title: Myocardial KChIP2 Expression in Guinea Pig Resolves an Expanded Electrophysiologic Role.
abstract: Cardiac ion channels and their respective accessory subunits are critical in maintaining proper electrical activity of the heart. Studies have indicated that the K+ channel interacting protein 2 (KChIP2), originally identified as an auxiliary subunit for the channel Kv4, a component of the transient outward K+ channel (Ito), is a Ca2+ binding protein whose regulatory function does not appear restricted to Kv4 modulation. Indeed, the guinea pig myocardium does not express Kv4, yet we show that it still maintains expression of KChIP2, suggesting roles for KChIP2 beyond this canonical auxiliary interaction with Kv4 to modulate Ito. In this study, we capitalize on the guinea pig as a system for investigating how KChIP2 influences the cardiac action potential, independent of effects otherwise attributed to Ito, given the endogenous absence of the current in this species. By performing whole cell patch clamp recordings on isolated adult guinea pig myocytes, we observe that knock down of KChIP2 significantly prolongs the cardiac action potential. This prolongation was not attributed to compromised repolarizing currents, as IKr and IKs were unchanged, but was the result of enhanced L-type Ca2+ current due to an increase in Cav1.2 protein. In addition, cells with reduced KChIP2 also displayed lowered INa from reduced Nav1.5 protein. Historically, rodent models have been used to investigate the role of KChIP2, where dramatic changes to the primary repolarizing current Ito may mask more subtle effects of KChIP2. Evaluation in the guinea pig where Ito is absent, has unveiled additional functions for KChIP2 beyond its canonical regulation of Ito, which defines KChIP2 as a master regulator of cardiac repolarization and depolarization.
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Drew M
authors.initials: DM
authors.lastname: Nassal
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wan
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Heart and Vascular Research Center, Department of Medicine, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio, United States of America.|Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Deschênes
mesh_terms: D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D051381:Rats
chemical_list: D020746:Calcium Channels, L-Type; D051605:Kv Channel-Interacting Proteins