Electrophysiological Role of Voltage-gated Sodium Channel B2 Subunits in the Heart.

Voltage-gated sodium channel β subunit;Cardiac arrhythmia;Brugada syndrome;Atrial fibrillation;Physiology;Health Sciences;Pharmacology

Bao, YangyangLopatin, Anatoli ;

University of Michigan

关键词: Voltage-gated sodium channel β subunit;    Cardiac arrhythmia;    Brugada syndrome;    Atrial fibrillation;    Physiology;    Health Sciences;    Pharmacology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/116738/baoyy_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Voltage-gated sodium channels (VGSCs) are critical for impulse initiation and propagation in excitable cells, including nerve and muscle. The ion-conducting VGSC α subunits are modulated by two β subunits that do not form the pore but play essential roles in electrical signal transduction. VGSC β subunits signal through multiple pathways on multiple time scales in vivo and are essential for life. In addition to regulating sodium current, β subunits associate with potassium channels and play non-conducting roles as cell adhesion molecules (CAMs) that participate in cell-cell coupling and macromolecular complex formation. Mutations in genes encoding VGSC β subunits disrupt both sodium and potassium channel complexes as well as cell-cell communication, leading to heart and brain diseases that can be catastrophic. In my PhD thesis work, I particularly focused on Scn2b, which encodes β2. Mutations in SCN2B have been associated with atrial fibrillation and Brugada syndrome. Thus, β2 may play critical roles in cardiac electrical activity in vivo. To understand the pathophysiological roles of β2 in the heart. I investigated the cardiac phenotype of Scn2b null mice. I observed loss of sodium current in ventricular myocytes, likely at the intercalated discs, leading to conduction slowing in the right ventricular outflow tract (RVOT) region. Functional re-entry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes (PVCs), was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. The cardiac conduction system was intact in Scn2b null hearts, with a slowed heart rate, likely due to altered autonomic control. Finally, Scn2b null atria were more susceptible to atrial fibrillation due to increased levels of fibrosis and higher repolarization dispersion than wild type littermates. In conclusion, genetic deletion of Scn2b in mice produces an arrhythmogenic phenotype similar to Brugada syndrome with increased susceptibility to atrial arrhythmia. This study provides insight into the role of β2 in maintaining normal cardiac electrical activity, introduces a murine model to understand the mechanism of human Brugada syndrome, and provides a novel understanding of the connection between Brugada syndrome and atrial fibrillation in patients who carry sodium channel mutations.