Ankyrin-G Coordinates Intercalated Disc Signaling Platform to Regulate Cardiac Excitability In Vivo

作者：Makara Michael A; Curran Jerry; Little Sean C; Musa Hassan; Polina Iuliia; Smith Sakima A; Wright Patrick J; Unudurthi Sathya D; Snyder Jed; Bennett Vann; Hund Thomas J; Mohler Peter J^*

来源：Circulation Research, 2014, 115(11): 929-+.

DOI：10.1161/CIRCRESAHA.115.305154

• ankyrin
• arrhythmia (mechanisms)
• cell biology
• mouse mutant
• Nav1.5
• protein trafficking
• sodium channels
• targeting

Rationale: 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, beta(IV)-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-delta; however, beta(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 beta-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. (Circ Res. 2014;115:929-938.)

• 出版日期2014-11-7