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

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

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

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 v1.3) 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 Ca v1.3. 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.

Original languageEnglish (US)
Pages (from-to)1212-1222
Number of pages11
JournalCirculation
Volume124
Issue number11
DOIs
StatePublished - Sep 13 2011

Keywords

  • Arrhythmia (mechanisms)
  • cytoskeleton
  • ion channel
  • protein trafficking

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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