NFATc3-dependent loss of I(to) gradient across the left ventricular wall during chronic beta adrenergic stimulation.
In heart, pore-forming Kv4 alpha 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 beta adrenergic signaling. [Ca(2+)](i), calcineurin, and NFAT activity were larger in ENDO than in EPI myocytes. Infusion of the beta adrenergic receptor agonist isoproterenol increased [Ca(2+)](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 beta1 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 beta adrenergic stimulation.
Rossow
Charles F
CF
Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195, USA.
Dilly
Keith W
KW
Yuan
Can
C
Nieves-Cintrón
Madeline
M
Cabarrus
Jennifer L
JL
Santana
Luis F
LF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D006352:Heart Ventricles / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051672:Shal Potassium Channels / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D050778:NFATC Transcription Factors; D051672:Shal Potassium Channels; C445503:transcription factor NF-AT c3; D019703:Calcineurin; D007545:Isoproterenol; D002118:Calcium