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Cardiovascular Research Advance Access first published online on October 1, 2009
This version [Corrected Proof] published online on October 30, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp324
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes{dagger}

Takeshi Aiba, Geoffrey G. Hesketh, Ting Liu, Rachael Carlisle, Maria Celeste Villa-Abrille, Brian O'Rourke, Fadi G. Akar and Gordon F. Tomaselli*

Division of Cardiology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 844, Baltimore, MD 21205, USA

* Corresponding author. Tel: +1 410 955 2774, Fax: +1 410 502 2096, Email: gtomasel{at}jhmi.edu

Aims: Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias. However, the acute effects of Ca2+/CaM and CaMKII on cardiac Na+ channels are not fully understood.

Methods and results: Purified NaV1.5–glutathione-S-transferase fusion peptides were phosphorylated in vitro by CaMKII predominantly on the I–II linker. Whole-cell voltage-clamp was used to measure Na+ current (INa) in isolated guinea-pig ventricular myocytes in the absence or presence of CaM or CaMKII in the pipette solution. CaMKII shifted the voltage dependence of Na+ channel availability by {approx}+5 mV, hastened recovery from inactivation, decreased entry into intermediate or slow inactivation, and increased persistent (late) current, but did not change INa decay. These CaMKII-induced changes of Na+ channel gating were completely abolished by a specific CaMKII inhibitor, autocamtide-2-related inhibitory peptide (AIP). Ca2+/CaM alone reproduced the CaMKII-induced changes of INa availability and the fraction of channels undergoing slow inactivation, but did not alter recovery from inactivation or the magnitude of the late current. Furthermore, the CaM-induced changes were also completely abolished by AIP. On the other hand, cAMP-dependent protein kinase A inhibitors did not abolish the CaM/CaMKII-induced alterations of INa function.

Conclusion: Ca2+/CaM and CaMKII have distinct effects on the inactivation phenotype of cardiac Na+ channels. The differences are consistent with CaM-independent effects of CaMKII on cardiac Na+ channel gating.

KEYWORDS Na-channel; Calcium; Calmodulin; Ca2+/CaM-dependent protein kinase II

Time for primary review: 22 days

{dagger} This study was presented in part at the Scientific Session of the Heart Rhythm Society, 9–12 May 2007, and published in abstract form [Heart Rhythm 2007;4(Suppl. 149)].


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