title: Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.
abstract: BACKGROUND
  Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated.
  
  
  RESULTS
  We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium.
  
  
  CONCLUSIONS
  We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Medical Center, 473 W 12th Ave, Columbus, OH 43210, USA.
authors.forename: Olha M
authors.initials: OM
authors.lastname: Koval
authors.forename: Jedidiah S
authors.initials: JS
authors.lastname: Snyder
authors.forename: Roseanne M
authors.initials: RM
authors.lastname: Wolf
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.forename: Patric
authors.initials: P
authors.lastname: Glynn
authors.forename: Jerry
authors.initials: J
authors.lastname: Curran
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Leymaster
authors.forename: Wen
authors.initials: W
authors.lastname: Dun
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wright
authors.forename: Natalia
authors.initials: N
authors.lastname: Cardona
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Mitchell
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000235:genetics
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2