title: Reductions in the Cardiac Transient Outward K+ Current Ito Caused by Chronic β-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor κB.
abstract: The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming α-subunits, Kv4.2 and Kv4.3, together with the accessory β-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also associated with enhanced stimulation of β-adrenergic receptors (β-ARs). We used cultured neonatal rat ventricular myocytes to examine how chronic β-AR stimulation decreases Ito,f. To determine which downstream pathways mediate these Ito,f changes, adenoviral infections were used to inhibit CaMKIIδc, CaMKIIδb, calcineurin, or nuclear factor κB (NF-κB). We observed that chronic β-AR stimulation with isoproterenol (ISO) for 48 h reduced Ito,f along with mRNA expression of all three of its subunits (Kv4.2, Kv4.3, and KChIP2). Inhibiting either CaMKIIδc nor CaMKIIδb did not prevent the ISO-mediated Ito,f reductions, even though CaMKIIδc and CaMKIIδb clearly regulated Ito,f and the mRNA expression of its subunits. Likewise, calcineurin inhibition did not prevent the Ito,f reductions induced by β-AR stimulation despite strongly modulating Ito,f and subunit mRNA expression. In contrast, NF-κB inhibition partly rescued the ISO-mediated Ito,f reductions in association with restoration of KChIP2 mRNA expression. Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as β-AR stimulation. In conclusion, NF-κB, and not CaMKIIδ or calcineurin, partly mediates the Ito,f reductions induced by chronic β-AR stimulation. Both mRNA and KChIP2 promoter data suggest that the ISO-induced Ito,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-κB activation.
authors.affiliation: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada, the Masonic Medical Research Laboratory, Department of Experimental Cardiology, Utica, New York 13501, and.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Panama
authors.affiliation: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Korogyi
authors.affiliation: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Roozbeh
authors.initials: R
authors.lastname: Aschar-Sobbi
authors.affiliation: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Yena
authors.initials: Y
authors.lastname: Oh
authors.affiliation: the Department of Pharmacology, University of California, San Diego, California 92161.
authors.forename: Charles B B
authors.initials: CB
authors.lastname: Gray
authors.affiliation: The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada.
authors.forename: Hongying
authors.initials: H
authors.lastname: Gang
authors.affiliation: the Department of Pharmacology, University of California, San Diego, California 92161.
authors.forename: Joan Heller
authors.initials: JH
authors.lastname: Brown
authors.affiliation: The Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R2H 2A6, Canada.
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.affiliation: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada, the Division of Cardiology, University Health Network, University of Toronto, Toronto, Ontario M5G 1L7, Canada, pbackx@yorku.ca.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology*; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000235:genetics / Q000378:metabolism; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D000318:Adrenergic beta-Agonists; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D016328:NF-kappa B; D011941:Receptors, Adrenergic; D051672:Shal Potassium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D007545:Isoproterenol
keywords: Ca2+/calmodulin-dependent protein kinase (CaMK); adrenergic receptor; cardiomyocyte; potassium channel; transcription