Loss of Camp-Dependent Protein Kinase A (PKA)-Mediated Na Channel Phosphorylation and Brugada Syndrome

Takeshi Aiba, Federica Farinelli, Geoffrey Hesketh, Wataru Shimizu, Gordon F. Tomaselli

Research output: Contribution to journalArticle

Abstract

PKA phosphorylation is important for Nav1.5 expression and function, however little is known about the relationship between Brugada syndrome (BrS) phenotype and PKA. We characterized the biophysical properties of a novel BrS-associated SCN5A mutation, R526H, identified in a proband that was resuscitated from sudden cardiac death. Methods: Whole-cell currents through wild-type (WT) Nav1.5 and mutant (R526H) channels expressed in HEK293-cell were recorded using patch clamp. Results: No difference was found in the peak current, steady-state activation, inactivation and recovery from inactivation in WT and mutant channels at baseline. PKA-stimulation (forskolin+cAMP) 1.7-fold increased the peak Na current (p>0.01), hyperpolarized the activation curve (+13mV; p>0.01) and hastened recovery from inactivation of WT. In contrast, no difference was found in the peak Na current, activation and recovery from inactivation after PKA-stimulation in R526H or in the mutation of the PKA-phosphorylation site, S528A. Voltage-dependent availability was not altered by PKA in WT, R526H and S528A. Thus, PKA-stimulation 4-fold increased Na window current in WT but not the mutant channels. In-vitro PKA phosphorylation was detected in the I-II linker of WT but not R526H and S528A mutants of Nav1.5. Conclusion: R526H mutant eliminated phosphorylation of Nav1.5 and abolished the PKA-induced increase in current amplitude. The loss of PKA stimulation may result in the Brugada phenotype.

Original languageEnglish (US)
JournalJournal of Arrhythmia
Volume27
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

Brugada Syndrome
Cyclic AMP-Dependent Protein Kinases
Phosphorylation
Phenotype
Mutation
HEK293 Cells
Sudden Cardiac Death
Colforsin

Keywords

  • Na channel
  • phosphorylation
  • sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Loss of Camp-Dependent Protein Kinase A (PKA)-Mediated Na Channel Phosphorylation and Brugada Syndrome. / Aiba, Takeshi; Farinelli, Federica; Hesketh, Geoffrey; Shimizu, Wataru; Tomaselli, Gordon F.

In: Journal of Arrhythmia, Vol. 27, 01.01.2011.

Research output: Contribution to journalArticle

Aiba, Takeshi ; Farinelli, Federica ; Hesketh, Geoffrey ; Shimizu, Wataru ; Tomaselli, Gordon F. / Loss of Camp-Dependent Protein Kinase A (PKA)-Mediated Na Channel Phosphorylation and Brugada Syndrome. In: Journal of Arrhythmia. 2011 ; Vol. 27.
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