Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels
Stefan Wagner, Nataliya Dybkova, Eva C.L. Rasenack, Claudius Jacobshagen, Larissa Fabritz, Paulus Kirchhof, Sebastian K.G. Maier, Tong Zhang, Gerd Hasenfuss, Joan Heller Brown, Donald M. Bers, Lars S. Maier
Stefan Wagner, Nataliya Dybkova, Eva C.L. Rasenack, Claudius Jacobshagen, Larissa Fabritz, Paulus Kirchhof, Sebastian K.G. Maier, Tong Zhang, Gerd Hasenfuss, Joan Heller Brown, Donald M. Bers, Lars S. Maier
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Research Article Cardiology

Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels

Abstract

In heart failure (HF), Ca2+/calmodulin kinase II (CaMKII) expression is increased. Altered Na+ channel gating is linked to and may promote ventricular tachyarrhythmias (VTs) in HF. Calmodulin regulates Na+ channel gating, in part perhaps via CaMKII. We investigated effects of adenovirus-mediated (acute) and Tg (chronic) overexpression of cytosolic CaMKIIδC on Na+ current (INa) in rabbit and mouse ventricular myocytes, respectively (in whole-cell patch clamp). Both acute and chronic CaMKIIδC overexpression shifted voltage dependence of Na+ channel availability by –6 mV (P < 0.05), and the shift was Ca2+ dependent. CaMKII also enhanced intermediate inactivation and slowed recovery from inactivation (prevented by CaMKII inhibitors autocamtide 2–related inhibitory peptide [AIP] or KN93). CaMKIIδC markedly increased persistent (late) inward INa and intracellular Na+ concentration (as measured by the Na+ indicator sodium-binding benzofuran isophthalate [SBFI]), which was prevented by CaMKII inhibition in the case of acute CaMKIIδC overexpression. CaMKII coimmunoprecipitates with and phosphorylates Na+ channels. In vivo, transgenic CaMKIIδC overexpression prolonged QRS duration and repolarization (QT intervals), decreased effective refractory periods, and increased the propensity to develop VT. We conclude that CaMKII associates with and phosphorylates cardiac Na+ channels. This alters INa gating to reduce availability at high heart rate, while enhancing late INa (which could prolong action potential duration). In mice, enhanced CaMKIIδC activity predisposed to VT. Thus, CaMKII-dependent regulation of Na+ channel function may contribute to arrhythmogenesis in HF.

Authors

Stefan Wagner, Nataliya Dybkova, Eva C.L. Rasenack, Claudius Jacobshagen, Larissa Fabritz, Paulus Kirchhof, Sebastian K.G. Maier, Tong Zhang, Gerd Hasenfuss, Joan Heller Brown, Donald M. Bers, Lars S. Maier

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Figure 6

CaMKIIδc enhances late INa and increases [Na]i.

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CaMKIIδc enhances late INa and increases [Na]i. INa elic...
INa elicited at –20 mV (for 1,000 ms) was leak subtracted and normalized to peak INa. Current was integrated between 50 and 500 ms and normalized to the INa integral if no inactivation had occurred. (A) Original traces and mean data of normalized late INa. CaMKIIδC overexpression significantly increased late INa (reversed with KN93). (B) CaMKIIδC-Tg mice also showed late INa, but this was not reversible with KN93. Average peak INa was –10.2 ± 0.3 nA, –79.8 ± 2.7 pA/pF, Cm 132.7 ± 4 pF for rabbit and –14.3 ± 0.6 nA, –58.1 ± 2.8 pA/pF, Cm 259.7 ± 11.6 pF for mouse. (C) Mean [Na]i at different stimulation frequencies (left) and at 1 Hz (right) in rabbit myocytes. [Na]i was elevated in CaMKIIδc myocytes at all frequencies (P < 0.05) and reduced by KN93 (P < 0.05). (D) Mean data for CaMKIIδC-Tg mice also showing elevated [Na]i (versus WT; P < 0.05), but this was not reversed by KN93.