In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 115, No. 11 ( 2014-11-07), p. 929-938
Kurzfassung:
Na v 1.5 ( SCN5A ) is the primary cardiac voltage-gated Na v channel. Na v 1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Na v 1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Na v 1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Na v 1.5 membrane targeting, assembly, and regulation are still largely undefined. Objective: Define the in vivo mechanisms underlying Na v 1.5 membrane regulation. Methods and Results: Here, we define the molecular basis of an Na v channel regulatory platform in heart. Using new cardiac-selective ankyrin-G -/- mice (conditional knock-out mouse), we report that ankyrin-G targets Na v 1.5 and its regulatory protein calcium/calmodulin–dependent kinase II to the intercalated disc. Mechanistically, β IV -spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin–dependent kinase II-δ; however, β IV -spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Na v 1.5 expression/membrane localization and reduced I Na associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Na v channel antagonists. Moreover, we report that ankyrin-G links Na v channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to β-adrenergic stimulation. Conclusions: Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Na v 1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Na v 1.5.
Materialart:
Online-Ressource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.115.305154
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2014
ZDB Id:
1467838-X
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