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

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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 I Na 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 CaMKIIδ C 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.

Original languageEnglish (US)
Pages (from-to)3127-3138
Number of pages12
JournalJournal of Clinical Investigation
Volume116
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Tachycardia
Heart Failure
Calmodulin
Adenoviridae
Muscle Cells
Action Potentials
Heart Rate
Rabbits
Peptides

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wagner, S., Dybkova, N., Rasenack, E. C. L., Jacobshagen, C., Fabritz, L., Kirchhof, P., ... Maier, L. S. (2006). Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. Journal of Clinical Investigation, 116(12), 3127-3138. https://doi.org/10.1172/JCI26620

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

In: Journal of Clinical Investigation, Vol. 116, No. 12, 01.12.2006, p. 3127-3138.

Research output: Contribution to journalArticle

Wagner, S, Dybkova, N, Rasenack, ECL, Jacobshagen, C, Fabritz, L, Kirchhof, P, Maier, SKG, Zhang, T, Hasenfuss, G, Brown, JH, Bers, DM & Maier, LS 2006, 'Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels', Journal of Clinical Investigation, vol. 116, no. 12, pp. 3127-3138. https://doi.org/10.1172/JCI26620
Wagner S, Dybkova N, Rasenack ECL, Jacobshagen C, Fabritz L, Kirchhof P et al. Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. Journal of Clinical Investigation. 2006 Dec 1;116(12):3127-3138. https://doi.org/10.1172/JCI26620
Wagner, Stefan ; Dybkova, Nataliya ; Rasenack, Eva C L ; Jacobshagen, Claudius ; Fabritz, Larissa ; Kirchhof, Paulus ; Maier, Sebastian K G ; Zhang, Tong ; Hasenfuss, Gerd ; Brown, Joan Heller ; Bers, Donald M ; Maier, Lars S. / Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 12. pp. 3127-3138.
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AU - Wagner, Stefan

AU - Dybkova, Nataliya

AU - Rasenack, Eva C L

AU - Jacobshagen, Claudius

AU - Fabritz, Larissa

AU - Kirchhof, Paulus

AU - Maier, Sebastian K G

AU - Zhang, Tong

AU - Hasenfuss, Gerd

AU - Brown, Joan Heller

AU - Bers, Donald M

AU - Maier, Lars S.

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N2 - 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 I Na 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 CaMKIIδ C 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.

AB - 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 I Na 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 CaMKIIδ C 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.

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