NFATc3-dependent loss of Ito gradient across the left ventricular wall during chronic β adrenergic stimulation

In heart, pore-forming Kv4 α channel subunits underlie the K⁺ transient outward current (I_to). Expression of Kv4 is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells, resulting in larger I_to in EPI than in ENDO cells. In adult ventricular myocytes, the transcription factor NFATc3 suppresses Kv4 expression. NFATc3 activity is higher in ENDO than in EPI cells and this has been proposed to contribute to heterogeneous Kv4 expression across the left ventricular free wall. Here, we tested the hypothesis that regional activation of NFATc3 signaling dissipates the gradient of I_to density across the mouse left ventricle during chronic activation of β adrenergic signaling. [Ca²⁺]_i, calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the β adrenergic receptor agonist isoproterenol increased [Ca²⁺]_i, calcineurin, and NFAT activity in EPI, but not in ENDO myocytes, leading to equalization of these parameters in EPI and ENDO cells. This was accompanied by dissipation of the transmural gradient in Kv4.2 expression and I_to density. Unlike wild type, ENDO or EPI myocytes from β1 adrenergic receptor-null and NFATc3-null mice did not undergo changes in I_to density during isoproterenol infusion. Collectively, these data suggest that calcineurin and NFATc3 signaling contributes to the loss of heterogeneous Kv4 expression, and hence I_to density, in the mouse left ventricle during chronic β adrenergic stimulation.