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

Research output: Contribution to journalArticlepeer-review

358 Scopus citations

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

ASJC Scopus subject areas

  • Medicine(all)

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