NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction.
Reductions in voltage-activated K+ (Kv) currents may underlie arrhythmias after myocardial infarction (MI). We investigated the role of beta-adrenergic signaling and the calcineurin/NFAT pathway in mediating the reductions in Kv currents observed after MI in mouse ventricular myocytes. Kv currents were produced by the summation of 3 distinct currents: I(to), I(Kslow1), and I(Kslow2). At 48 hours after MI, we found a 4-fold increase in NFAT activity, which coincided with a decrease in the amplitudes of I(to), I(Kslow1), and I(Kslow2). Consistent with this, mRNA and protein levels of Kv1.5, 2.1, 4.2, and 4.3, which underlie I(Kslow1), I(Kslow2), and I(to), were decreased after MI. Administration of the beta-blocker metoprolol prevented the activation of NFAT and the reductions in I(to), I(Kslow1), and I(Kslow2) after MI. Cyclosporine, an inhibitor of calcineurin, also prevented the reductions in these currents after MI. Importantly, Kv currents did not change after MI in ventricular myocytes from NFATc3 knockout mice. Conversely, chronic beta-adrenergic stimulation or expression of an activated NFATc3 decreased Kv currents to a similar extent as MI. Taken together, these data indicate that NFATc3 plays an essential role in the signaling pathway leading to reduced I(to), I(Kslow1), and I(Kslow2) after MI. We propose that increased beta-adrenergic signaling after MI activates calcineurin and NFATc3, which decreases I(to), I(Kslow1), and I(Kslow2) via a reduction in Kv1.5, Kv2.1, Kv4.2, and Kv4.3 expression.
Rossow
Charles F
CF
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.
Minami
Elina
E
Chase
Eric G
EG
Murry
Charles E
CE
Santana
L F
LF
D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004553:Electric Conductivity; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D050778:NFATC Transcription Factors; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D024642:Potassium Channels, Voltage-Gated; D014157:Transcription Factors; C445503:transcription factor NF-AT c3; D016572:Cyclosporine; D008790:Metoprolol; D007545:Isoproterenol