Loss of Camp-Dependent Protein Kinase A (PKA)-Mediated Na Channel Phosphorylation and Brugada Syndrome
スポンサーリンク
概要
- 論文の詳細を見る
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. <B>Methods:</B> Whole-cell currents through wild-type (WT) Nav1.5 and mutant (R526H) channels expressed in HEK293-cell were recorded using patch clamp. <B>Results:</B> 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 (+13 mV; 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. <B>Conclusion:</B> 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.
著者
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Hesketh Geoffrey
Division Of Cardiology Johns Hopkins University School Of Medicine
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Shimizu Wataru
Division Of Arrhythmia And Electrophysiology Department Of Cardiology National Cerebral And Cardiova
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Aiba Takeshi
Division Of Arrhythmia And Electrophysiology Department Of Cardiology National Cerebral And Cardiova
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Tomaselli Gordon
Division Of Cardiology Johns Hopkins University School Of Medicine
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Hesketh Geoffrey
Division of Cardiology, Johns Hopkins Medical Institutions
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Farinelli Federica
Division of Cardiology, Johns Hopkins Medical Institutions
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Tomaselli Gordon
Division of Cardiology, Johns Hopkins Medical Institutions
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