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...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
22 Aug 2011
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| In: |
Circulation
Year: 2011, Jahrgang: 124, Heft: 11, Pages: 1212-1222 |
| ISSN: | 1524-4539 |
| DOI: | 10.1161/CIRCULATIONAHA.111.023986 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1161/CIRCULATIONAHA.111.023986 Verlag, lizenzpflichtig, Volltext: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.023986 
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| Verfasserangaben: | 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 |
MARC
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| 245 | 1 | 0 | |a Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation |c 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 |
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| 520 | |a 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. | ||
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