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http://purl.uniprot.org/citations/30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/30544220http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.org/dc/terms/identifier"doi:10.1093/cvr/cvy310"xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Davis J."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Guo J."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Li W."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Zhang S."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Yang T."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Lamothe S.M."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Vanner S."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Baranchuk A."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Joneja M."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/author"Szendrey J."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/date"2019"xsd:gYear
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/name"Cardiovasc Res"xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/pages"1500-1511"xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/title"Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression."xsd:string
http://purl.uniprot.org/citations/30544220http://purl.uniprot.org/core/volume"115"xsd:string
http://purl.uniprot.org/citations/30544220http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/30544220
http://purl.uniprot.org/citations/30544220http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/30544220
http://purl.uniprot.org/uniprot/#_A0A090N7W1-mappedCitation-30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30544220
http://purl.uniprot.org/uniprot/#_A0A090N7X5-mappedCitation-30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30544220
http://purl.uniprot.org/uniprot/#_A0A090N8Q0-mappedCitation-30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30544220
http://purl.uniprot.org/uniprot/#_C7DYB4-mappedCitation-30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30544220
http://purl.uniprot.org/uniprot/#_A0PJW5-mappedCitation-30544220http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/30544220
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