Journal article
Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation
Circulation (New York, N.Y.), Vol.124(11), pp.1212-1222
09/13/2011
DOI: 10.1161/CIRCULATIONAHA.111.023986
PMCID: PMC3211046
PMID: 21859974
Abstract
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 (Ca(v)1.3) responsible for low voltage-activated L-type Ca2+ 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. (Circulation. 2011;124:1212-1222.)
Details
- Title: Subtitle
- Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation
- Creators
- Shane R. Cunha - The Ohio State UniversityThomas J. Hund - The Ohio State UniversitySeyed Hashemi - University of IowaNiels Voigt - Heidelberg UniversityNa Li - Baylor College of MedicinePatrick Wright - The Ohio State UniversityOlha Koval - University of IowaJingdong Li - The Ohio State UniversityHjalti Gudmundsson - University of IowaRichard J. Gumina - The Ohio State UniversityMatthias Karck - Heidelberg UniversityJean-Jacques Schott - Nantes UniversitéVincent Probst - Nantes UniversitéHerve Le Marec - Nantes UniversitéMark E. Anderson - University of IowaDobromir Dobrev - Heidelberg UniversityXander H. T. Wehrens - Baylor College of MedicinePeter J. Mohler - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.124(11), pp.1212-1222
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/CIRCULATIONAHA.111.023986
- PMID
- 21859974
- PMCID
- PMC3211046
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Number of pages
- 11
- Grant note
- 261057 / European Union through the European Network for Translational Research in Atrial Fibrillation (EUTRAF) Pew Scholars Trust American Heart Association HL084583; HL083422; HL079031; HL 62494; HL70250; HL089598; HL091947; HL096805; HL092232; HL094703; HL096038 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Gilead; Gilead Sciences Fondation Leducq; Leducq Foundation W.M. Keck Foundation R01HL070250 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 09/13/2011
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984360153502771
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