Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/20224043http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/20224043http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in a well-defined region of the cardiac type 2 ryanodine receptor (RyR)2. However, the underlying mechanism by which a single mutation in such a large molecule produces drastic effects on channel function remains unresolved.

Objective

Using a knock-in (KI) mouse model with a human CPVT-associated RyR2 mutation (R2474S), we investigated the molecular mechanism by which CPVT is induced by a single point mutation within the RyR2.

Methods and results

The R2474S/+ KI mice showed no apparent structural or histological abnormalities in the heart, but they showed clear indications of other abnormalities. Bidirectional or polymorphic ventricular tachycardia was induced after exercise on a treadmill. The interaction between the N-terminal (amino acids 1 to 600) and central (amino acids 2000 to 2500) domains of the RyR2 (an intrinsic mechanism to close Ca(2+) channels) was weakened (domain unzipping). On protein kinase A-mediated phosphorylation of the RyR2, this domain unzipping further increased, resulting in a significant increase in the frequency of spontaneous Ca(2+) transients. cAMP-induced aberrant Ca(2+) release events (Ca(2+) sparks/waves) occurred at much lower sarcoplasmic reticulum Ca(2+) content as compared to the wild type. Addition of a domain-unzipping peptide, DPc10 (amino acids 2460 to 2495), to the wild type reproduced the aforementioned abnormalities that are characteristic of the R2474S/+ KI mice. Addition of DPc10 to the (cAMP-treated) KI cardiomyocytes produced no further effect.

Conclusions

A single point mutation within the RyR2 sensitizes the channel to agonists and reduces the threshold of luminal [Ca(2+)] for activation, primarily mediated by defective interdomain interaction within the RyR2."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.109.209312"xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Oda T."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Matsuzaki M."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Kobayashi S."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Yamamoto T."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Xu X."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Yano M."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Ikeda Y."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Ono M."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Doi M."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Okuda S."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Ohkusa T."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Tateishi H."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Ikemoto N."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Suetomi T."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/author"Uchinoumi H."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/pages"1413-1424"xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/title"Catecholaminergic polymorphic ventricular tachycardia is caused by mutation-linked defective conformational regulation of the ryanodine receptor."xsd:string
http://purl.uniprot.org/citations/20224043http://purl.uniprot.org/core/volume"106"xsd:string
http://purl.uniprot.org/citations/20224043http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/20224043
http://purl.uniprot.org/citations/20224043http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/20224043
▶