Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo

Circulation. 2015 Aug 18;132(7):567-77. doi: 10.1161/CIRCULATIONAHA.114.015218. Epub 2015 Jul 17.


Background: Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown.

Methods and results: To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload.

Conclusions: Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.

Keywords: Na+ current; action potential; arrhythmias, cardiac; calcium-calmodulin-dependent protein kinase type 2; ion channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / pharmacology
  • Action Potentials
  • Animals
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / physiopathology*
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cardiomegaly / physiopathology
  • Constriction
  • Gene Knock-In Techniques
  • Ion Channel Gating / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NAV1.5 Voltage-Gated Sodium Channel / chemistry
  • NAV1.5 Voltage-Gated Sodium Channel / physiology*
  • Phosphorylation
  • Phosphoserine / metabolism*
  • Piperazines / pharmacology
  • Protein Processing, Post-Translational
  • Ranolazine
  • Sodium / metabolism
  • Sodium Channel Blockers / pharmacology
  • Ventricular Remodeling / physiology*


  • Acetanilides
  • NAV1.5 Voltage-Gated Sodium Channel
  • Piperazines
  • Scn5a protein, mouse
  • Sodium Channel Blockers
  • Phosphoserine
  • Sodium
  • Ranolazine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium