Cover Image

Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation

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 multif...

Full description

Saved in:
Bibliographic Details
Main Authors: Cunha, Shane R. (Author) , Hund, Thomas J. (Author) , Hashemi, Seyed (Author) , Voigt, Niels (Author) , Li, Na (Author) , Wright, Patrick (Author) , Koval, Olha (Author) , Li, Jingdong (Author) , Gudmundsson, Hjalti (Author) , Gumina, Richard J. (Author) , Karck, Matthias (Author) , Schott, Jean-Jacques (Author) , Probst, Vincent (Author) , Le Marec, Herve (Author) , Anderson, Mark E. (Author) , Dobrev, Dobromir (Author) , Wehrens, Xander H.T. (Author) , Mohler, Peter J. (Author)
Format: Article (Journal)
Language:English
Published: 22 Aug 2011
In: Circulation
Year: 2011, Volume: 124, Issue: 11, Pages: 1212-1222
ISSN:1524-4539
DOI:10.1161/CIRCULATIONAHA.111.023986
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCULATIONAHA.111.023986
Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.023986
Get full text
Author Notes:Shane R. Cunha, Thomas J. Hund, Seyed Hashemi, Niels Voigt, Na Li, Patrick Wright, Olha Koval, Jingdong Li, Hjalti Gudmundsson, Richard J. Gumina, Matthias Karck, Jean-Jacques Schott, Vincent Probst, Herve Le Marec, Mark E. Anderson, Dobromir Dobrev, Xander H.T. Wehrens, Peter J. Mohler
Description
Summary: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 Ca2+ channels (Cav1.3) responsible for low voltage-activated L-type Ca2+ current. Ankyrin-B is associated directly with Cav1.3, and this interaction is regulated by a short, highly conserved motif specific to Cav1.3. Moreover, loss of ankyrin-B in atrial myocytes results in decreased Cav1.3 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 Cav1.3 channel membrane targeting and regulation in atrial myocytes.
Item Description:Gesehen am 21.04.2022
Physical Description:Online Resource
ISSN:1524-4539
DOI:10.1161/CIRCULATIONAHA.111.023986

Similar Items