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http://purl.uniprot.org/citations/21859974http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/21859974http://www.w3.org/2000/01/rdf-schema#comment"

Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting >2 million patients in the United States alone. Despite decades of research, surprisingly little is known regarding the molecular pathways underlying the pathogenesis of AF. ANK2 encodes ankyrin-B, a multifunctional adapter molecule implicated in membrane targeting of ion channels, transporters, and signaling molecules in excitable cells.

Methods and results

In the present study, we report early-onset AF in patients harboring loss-of-function mutations in ANK2. In mice, we show that ankyrin-B deficiency results in atrial electrophysiological dysfunction and increased susceptibility to AF. Moreover, ankyrin-B(+/-) atrial myocytes display shortened action potentials, consistent with human AF. Ankyrin-B is expressed in atrial myocytes, and we demonstrate its requirement for the membrane targeting and function of a subgroup of voltage-gated Ca(2+) channels (Ca(v)1.3) responsible for low voltage-activated L-type Ca(2+) current. Ankyrin-B is associated directly with Ca(v)1.3, and this interaction is regulated by a short, highly conserved motif specific to Ca(v)1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Ca(v)1.3 expression, membrane localization, and function sufficient to produce shortened atrial action potentials and arrhythmias. Finally, we demonstrate reduced ankyrin-B expression in atrial samples of patients with documented AF, further supporting an association between ankyrin-B and AF.

Conclusions

These findings support that reduced ankyrin-B expression or mutations in ANK2 are associated with AF. Additionally, our data demonstrate a novel pathway for ankyrin-B-dependent regulation of Ca(v)1.3 channel membrane targeting and regulation in atrial myocytes."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.111.023986"xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Li J."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Li N."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Anderson M.E."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Le Marec H."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Mohler P.J."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Gumina R.J."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Hund T.J."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Schott J.J."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Cunha S.R."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Gudmundsson H."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Wright P."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Karck M."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Probst V."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Dobrev D."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Voigt N."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Wehrens X.H."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Hashemi S."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/author"Koval O."xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/date"2011"xsd:gYear
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/pages"1212-1222"xsd:string
http://purl.uniprot.org/citations/21859974http://purl.uniprot.org/core/title"Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation."xsd:string
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