Details

Autor(en) / Beteiligte

• CUNHA, Shane R
• HUND, Thomas J
• KARCK, Matthias
• SCHOTT, Jean-Jacques
• PROBST, Vincent
• LE MAREC, Herve
• ANDERSON, Mark E
• DOBREV, Dobromir
• WEHRENS, Xander H. T
• MOHLER, Peter J
• HASHEMI, Seyed
• VOIGT, Niels
• NA LI
• WRIGHT, Patrick
• KOVAL, Olha
• JINGDONG LI
• GUDMUNDSSON, Hjalti
• GUMINA, Richard J

Titel

Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation

Ist Teil von

• Circulation (New York, N.Y.), 2011-09, Vol.124 (11), p.1212-1222

Ort / Verlag

Hagerstown, MD: Lippincott Williams & Wilkins

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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.