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Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression.


ABSTRACT: AIMS:The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr). Malfunction of hERG/IKr is the primary cause of acquired long QT syndrome (LQTS), an electrical disorder of the heart that can cause arrhythmias and sudden death. Patients with autoimmune diseases display a high incidence of LQTS. While dysfunction of hERG channels induced by autoantibodies such as anti-Ro52 may play a role in this pathology, the underlying mechanisms are not well understood. Here, we investigated the acute and chronic effects of anti-Ro52 antibody on hERG channels stably expressed in human embryonic kidney (hERG-HEK) 293 cells as well as IKr in neonatal rat ventricular myocytes. METHODS AND RESULTS:Using whole-cell patch clamp, western blot analyses, and immunocytochemistry, we found that a 12-h treatment of hERG-HEK cells with patients' sera containing anti-Ro52 autoantibody decreased the hERG current (IhERG) by 32% compared to cells treated with autoantibody-negative patients' sera. Commercial anti-Ro52 antibody at 100?µg/mL did not acutely block IhERG. Instead, a 12-h treatment with anti-Ro52 antibody at a concentration of 4?µg/mL significantly reduced mature hERG protein expression and IhERG. Specifically, anti-Ro52 antibody did not acutely block hERG current but chronically facilitated hERG endocytic degradation. The extracellular S5-pore linker of hERG, which forms the turret of the channel on the outside of the cell, is the target region for anti-Ro52-mediated hERG reduction since its replacement with the analogous region of EAG abolished the anti-Ro52 effect. In neonatal rat ventricular myocytes, 100?µg/mL anti-Ro52 antibody did not acutely block IKr, but a 12-h treatment of cells with 4?µg/mL anti-Ro52 antibody selectively reduced IKr and prolonged the action potential duration. CONCLUSIONS:Our results indicate that anti-Ro52 antibody acts on the hERG S5-pore linker to chronically decrease hERG expression and current. These findings provide novel insights into hERG regulation and anti-Ro52 antibody-associated LQTS.

SUBMITTER: Szendrey J 

PROVIDER: S-EPMC6648346 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression.

Szendrey John J   Lamothe Shawn M SM   Vanner Stephanie S   Guo Jun J   Yang Tonghua T   Li Wentao W   Davis Jordan J   Joneja Mala M   Baranchuk Adrian A   Zhang Shetuan S  

Cardiovascular research 20190801 10


<h4>Aims</h4>The human ether-a-go-go-related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr). Malfunction of hERG/IKr is the primary cause of acquired long QT syndrome (LQTS), an electrical disorder of the heart that can cause arrhythmias and sudden death. Patients with autoimmune diseases display a high incidence of LQTS. While dysfunction of hERG channels induced by autoantibodies such as anti-Ro52 may play a role in this pathology, the underlying mechanism  ...[more]

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