Reductions in voltage-activated K ϩ (Kv) currents may underlie arrhythmias after myocardial infarction (MI). We investigated the role of ␤-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

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... s 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 ␤-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 ␤-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 ␤-adrenergic signaling after MI activates calcineurin and NFATc3, which decreases I to , I Kslow1 , and I Kslow2 via a reduction in Figure 5. MI does not decrease I to , I Kslow1 , and I Kslow2 in NFATc3-KO ventricular myocytes. A, Representative Kv currents from NFATc3-KO, NFATc3-KO-MI, and WT-MI cells. B to F, Current-voltage relationships of I tran , I sust , I Kslow1 , I Kslow2 , and I to in NFATc3-KO, NFATc3-KO-MI, and WT-MI cells. G, Real-time RT-PCR analysis of Kv1.5, 2.1, 4.2, and 4.3 mRNA in NFATc3-KO and NFATc3-KO-MI hearts. H, Western blots of Kv1.5, Kv2.1, Kv4.2, and Kv4.3 protein in NFATc3-KO and NFATc3-KO-MI cells. The bar plot shows the percent change (relative to NFATc3-KO) in Kv protein after MI in NFATc3-KO cells. *PϽ0.05 vs MI.