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Changes in ion channel expression and function associated with cardiac arrhythmogenic remodeling by Sorbs2
Ling-Ling Qian1, Xiaojing Sun2, Jingchun Yang3
1The Departments of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA; Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA.
Biochimica Et Biophysica Acta. Molecular Basis of Disease
|September 6, 2021
Summary
Loss of Sorbin and SH3 domain-containing protein 2 (Sorbs2) causes cardiac structural and electrical remodeling, leading to fatal arrhythmias in mice. Sorbs2 deficiency disrupts cardiac ion channel function, causing arrhythmogenic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cardiac Electrophysiology
Background:
- Sorbin and SH3 domain-containing protein 2 (Sorbs2) is a cardiomyocyte sarcomere component.
- Sorbs2 deficiency is linked to human arrhythmogenic cardiomyopathy.
- The ionic mechanisms underlying Sorbs2 deficiency-induced arrhythmias are unknown.
Purpose of the Study:
- To investigate the role of Sorbs2 in regulating cardiac ion channel expression and function.
- To elucidate the ionic mechanisms of cardiac arrhythmogenesis in Sorbs2-deficient mice.
Main Methods:
- Electrophysiological studies (ECG, intracellular recordings, patch clamp) in Sorbs2 knockout (KO) mice.
- Molecular biological approaches to assess ion channel expression and interaction with Sorbs2.
- In vitro studies to determine Sorbs2's direct regulatory effects on ion channels.
Main Results:
- Sorbs2 KO mice exhibited progressive cardiac structural and electrical remodeling, premature death, and severe arrhythmias.
- Abnormal action potentials and altered expression/function of key cardiac ion channels (Na+, Ca2+, K+) were observed in Sorbs2 KO mice.
- Sorbs2 was found to physically interact with cardiac ion channel RNAs/proteins, directly regulating their expression.
Conclusions:
- Sorbs2 plays a critical role in maintaining cardiac ion channel physiology.
- Sorbs2 deficiency leads to cardiac ion channelopathies and life-threatening arrhythmias.
- Sorbs2 is a pivotal regulator of cardiac electrical function and a potential therapeutic target for arrhythmias.