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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
Published on: March 12, 2013
Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias
Yangyang Bao1, B Cicero Willis1, Chad R Frasier1
1From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).
Background:
Mutations in SCN2B, encoding voltage-gated sodium channel β2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo.
Methods And Results:
To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Nav1.5 protein, suggesting that similar to the previous work in neurons, the major function of β2-subunits in the ventricle is to chaperone voltage-gated sodium channel α-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates.
Conclusions:
Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.
Insights
Genetic deletion of SCN2B (sodium channel beta2-subunit) in mice caused cardiac arrhythmias, including atrial fibrillation and ventricular tachycardia. This highlights the critical role of SCN2B in maintaining normal heart electrical activity.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Ion Channel Physiology
Background:
- Mutations in SCN2B, encoding voltage-gated sodium channel beta2-subunits, are linked to human cardiac arrhythmias like atrial fibrillation and Brugada syndrome.
- This suggests a critical role for beta2-subunits in normal cardiac electrical activity.
Purpose of the Study:
- To investigate the cardiac-specific functions of beta2-subunits.
- To elucidate the pathophysiological mechanisms underlying arrhythmias in Scn2b-deficient hearts.
Main Methods:
- Generation and characterization of Scn2b null mice.
- Electrophysiological recordings from isolated ventricular myocytes.
- Assessment of cardiac structure and function, including fibrosis and repolarization dispersion.
Main Results:
- Scn2b null mice exhibited reduced sodium and potassium current densities and conduction slowing in ventricular myocytes.
- Spontaneous polymorphic ventricular tachycardia was driven by functional reentry.
- Scn2b deletion led to region-specific effects, with atria showing normal sodium current but increased susceptibility to atrial fibrillation, fibrosis, and repolarization dispersion.
Conclusions:
- Genetic deletion of Scn2b in mice recapitulates human cardiac arrhythmias.
- Beta2-subunits are crucial for normal cardiac electrical function, potentially by chaperoning sodium channel alpha-subunits.
- Scn2b deficiency contributes to both ventricular and atrial arrhythmias through distinct mechanisms.
