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

Authors: Cunha, SR  Hund, TJ  Hashemi, S  Voigt, N  Li, N  Wright, P  Koval, O  Li, J  Gudmundsson, H  Gumina, RJ  Karck, M  Schott, JJ  Probst, V  Le Marec, H  Anderson, ME  Dobrev, D  Wehrens, XH  Mohler, PJ 
Citation: Cunha SR, etal., Circulation. 2011 Sep 13;124(11):1212-22. Epub 2011 Aug 22.
Pubmed: (View Article at PubMed) PMID:21859974
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.111.023986

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.

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CRRD Object Information
CRRD ID: 6767284
Created: 2012-07-05
Species: All species
Last Modified: 2012-07-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.