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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.

J Biol Chem. 2016 Feb 19;291(8):4156-65. Epub 2016 Jan 07
Brian K Panama 1 , Adam S Korogyi 2 , Roozbeh Aschar-Sobbi 2 , Yena Oh 2 , Charles B B Gray 3 , Hongying Gang 4 , Joan Heller Brown 3 , Lorrie A Kirshenbaum 4 , Peter H Backx 5
Brian K Panama 1 , Adam S Korogyi 2 , Roozbeh Aschar-Sobbi 2 , Yena Oh 2 , Charles B B Gray 3 , Hongying Gang 4 , Joan Heller Brown 3 , Lorrie A Kirshenbaum 4 , Peter H Backx 5
+ et al

[No authors listed]

Author information
  • 1 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.
  • 2 From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
  • 3 the Department of Pharmacology, University of California, San Diego, California 92161.
  • 4 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.
  • 5 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.

摘要


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.

KEYWORDS: Ca2+/calmodulin-dependent protein kinase (CaMK), adrenergic receptor, cardiomyocyte, potassium channel, transcription