Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Regulates Cardiac Sodium Channel NaV1.5 Gating by Multiple Phosphorylation Sites

Ashpole, Nicole M.; Herren, Anthony W.; Ginsburg, Kenneth S.; Brogan, Joseph D.; Johnson, Derrick E.; Cummins, Theodore R.; Bers, Donald M.; Hudmon, Andy

doi:10.1074/jbc.m111.322537

Cited by 146 publications

(204 citation statements)

References 50 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…Therefore, we surmised that the differences in the rate dependence of myocardial conduction and excitability are likely related to differences in Na channel activity rather than expression. In recent years, studies have focused on the intricate regulation of Nav1.5 activity by CaMKII,24, 25, 26, 27 a key calcium‐dependent kinase that is activated in MI. In particular, CAMKII activation was shown to modulate Na channel recovery from inactivation 27.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

View full text Add to dashboard Cite

Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

show abstract

Section: Resultsmentioning

confidence: 99%

“…CAMKII, a calcium‐sensitive kinase that is activated post‐MI, regulates Na channel activity in a rate‐dependent manner 24, 25, 27. In particular, CAMKII‐dependent phosphorylation of Nav1.5 alters I Na gating by reducing current availability at higher pacing rates 27.…”

Section: Discussionmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…Downstream targets of ROS include CaMKII, I Ca,L , and I Na,L . ROS-activated CaMKII causes I Ca,L and I Na,L augmentation through the regulation of calcium and sodium channel phosphorylation sites [27] . Xie et al [7,10] have demonstrated that both I Ca,L and I Na,L are required for ROSinduced EAD formation: activation of late I Na to reduce the repolarization reserve (ie, to prolong APD) and the modification of I Ca,L to enhance its reactivation properties to generate the EAD upstroke.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

Wang

Gao

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca 2+ overload in ventricular myocytes and to explore the underlying mechanisms. Methods: Hydrogen peroxide (H 2 O 2 , 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca 2+ ([Ca 2+ ] i ). Ca 2+ /calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltageactivated Na + and Ca 2+ currents were examined using whole-cell recording in myocytes. In addition, resveratrol markedly blunted H 2 O 2 -induced diastolic [Ca 2+ ] i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H 2 O 2 significantly enhanced the late Na + current (I Na,L ) and L-type Ca 2+ current (I Ca,L ) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H 2 O 2 -induced ROS production and CaMKII activation were significantly prevented by resveratrol. Conclusion: Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca 2+ overload through inhibition of I Na,L /I Ca,L , reduction of ROS generation, and prevention of CaMKII activation.

show abstract

“…Previous work has shown that the cardiac sodium channel Na V 1.5 can be modulated by intracellular Ca 2+ and by CaMKII-mediated phosphorylation, which have profound effects on channel inactivation and persistent sodium current (8,10,19). Elevated intracellular Ca 2+ has been demonstrated to evoke a depolarized shift in the voltage dependence of inactivation and suppression of persistent sodium current for cardiac Na V 1.5 channels (8,20).…”

Section: Strain-dependent Biophysical Properties Of Neuronal Sodium Cmentioning

confidence: 99%

“…Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6,7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8)(9)(10). Thus, differences in posttranslational modification of sodium channels may profoundly influence the physiology of excitable cells.…”

mentioning

confidence: 99%

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Thompson

Hawkins

Kearney

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Monogenic epilepsies with wide-ranging clinical severity have been associated with mutations in voltage-gated sodium channel genes. In the Scn2a Q54 mouse model of epilepsy, a focal epilepsy phenotype is caused by transgenic expression of an engineered Na V 1.2 mutation displaying enhanced persistent sodium current. Seizure frequency and other phenotypic features in Scn2a Q54 mice depend on genetic background. We investigated the neurophysiological and molecular correlates of strain-dependent epilepsy severity in this model. Scn2a Q54 mice on the C57BL/6J background (B6.Q54) exhibit a mild disorder, whereas animals intercrossed with SJL/J mice (F1.Q54) have a severe phenotype. Whole-cell recording revealed that hippocampal pyramidal neurons from B6.Q54 and F1.Q54 animals exhibit spontaneous action potentials, but F1.Q54 neurons exhibited higher firing frequency and greater evoked activity compared with B6.Q54 neurons. These findings correlated with larger persistent sodium current and depolarized inactivation in neurons from F1.Q54 animals. Because calcium/calmodulin protein kinase II (CaMKII) is known to modify persistent current and channel inactivation in the heart, we investigated CaMKII as a plausible modulator of neuronal sodium channels. CaMKII activity in hippocampal protein lysates exhibited a strain-dependence in Scn2a Q54 mice with higher activity in F1.Q54 animals. Heterologously expressed Na V 1.2 channels exposed to activated CaMKII had enhanced persistent current and depolarized channel inactivation resembling the properties of F1.Q54 neuronal sodium channels. By contrast, inhibition of CaMKII attenuated persistent current, evoked a hyperpolarized channel inactivation, and suppressed neuronal excitability. We conclude that CaMKII-mediated modulation of neuronal sodium current impacts neuronal excitability in Scn2a Q54 mice and may represent a therapeutic target for the treatment of epilepsy.epilepsy | voltage-gated sodium channel | CaMKII V oltage-gated sodium channels are essential for the generation and propagation of action potentials in excitable cells (1). These proteins exist as heteromultimeric complexes formed by a large pore-forming α-subunit and one or more auxiliary β-subunits (2). Function of voltage-gated sodium channels is influenced by multiple intracellular factors including protein-protein interactions, channel phosphorylation, and intracellular calcium. The auxiliary β-subunits and a family of FGF homologous factors (FHF) have been shown to modulate trafficking and functional properties of voltage-gated sodium channels (3-5). Both PKA and PKC have been shown to modulate neuronal voltage-gated sodium current function (6, 7). Finally, intracellular calcium, calmodulin, and calcium/calmodulin protein kinase II (CaMKII) have been shown to have drastic effects on the cardiac sodium channel (8-10). Thus, differences in posttranslational modification of sodium channels may profoundly influence the physiology of excitable cells.Mutations in genes encoding neuronal voltage-gated sodium ch...

show abstract

Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Regulates Cardiac Sodium Channel NaV1.5 Gating by Multiple Phosphorylation Sites

Abstract: Background: CaMKII is up-regulated in heart failure and modulates Na ϩ current (I Na ), yet the mechanism is unclear.

Cited by 146 publications

References 50 publications

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload

CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice

Contact Info

Product

Resources

About