The role of CaMKII-dependent augmented INa,L in arrhythmias during acute β-adrenergic stimulation

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The Ohio State University

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The heart has evolved elaborate pathways for adapting function to acute stress stimuli [e.g. sympathetic stimulation of β-adrenergic receptors (β-ARs)]. This “fight-or-flight” cardiac response to acute stress involves rapid changes in heart rate and contractility. However, βAR stimulation has been shown to enhance arrhythmogenesis due, in part, to induction of Ca2+ overload in cardiac myoctyes,1,2,3 although the precise mechanism remains unknown. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated in response to β adrenergic stimulation and phosphorylates a myriad of intracellular targets including the cardiac sodium channel (Nav1.5) to alter myocyte excitability and Ca2+ handling. Our group and others have shown that CaMKII-dependent phosphorylation of Nav1.5 at Ser571 selectively regulates late sodium current (INa,L) in vivo. CaMKII-dependent increases in INa,L are linked to cardiac dysfunction.4,5,18,19 We hypothesized that CaMKII-dependent phosphorylation of Nav1.5, and subsequent increases in INa,L, are essential for Ca2+ handling defects and acute arrhythmic response to β-AR stimulation. Using optical mapping, we show that CaMKII-dependent phosphorylation of Nav1.5 alters Ca2+ transients and arrhythmia susceptibility at baseline and in response to β-AR agonist isoproterenol. Our data demonstrate an important link between CaMKII-dependent phosphorylation of the Nav1.5 Ser571 site and Ca2+ handling and arrhythmogenesis in response to acute β-AR stimulation.



Arrhythmias, Optical Mapping, Beta-adrenergic stimulation, Late sodium current, CaMKII