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

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 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.

• Authors: 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
• Journal: Circulation (Circulation) Vol. 124 Issue 11 Pg. 1212-22 (Sep 13 2011) ISSN: 1524-4539 [Electronic] United States
• PMID: 21859974 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ANK2 protein, human
• Ankyrins
• Calcium Channels
• Cacna1d protein, rat

Topics

• Adult
• Aged
• Amino Acid Sequence
• Animals
• Ankyrins (biosynthesis, deficiency, genetics)
• Atrial Fibrillation (genetics, metabolism)
• Calcium Channels (deficiency, genetics)
• Child
• Female
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Molecular Sequence Data
• Myocytes, Cardiac (metabolism)
• Protein Transport (physiology)
• Rats
• Signal Transduction (physiology)
• Young Adult