Ankyrin-B deficiency and loss-of-function mutations in ANK2 are associated with early-onset atrial fibrillation through decreased Cav1.3 channel membrane targeting and function.
Does ankyrin-B deficiency increase susceptibility to atrial fibrillation through altered ion channel targeting?
Reduced ankyrin-B expression or ANK2 mutations are associated with atrial fibrillation via a novel pathway involving Cav1.3 channel membrane targeting.
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.
Cunha et al. (Tue,) conducted a other in Atrial fibrillation. ANK2 loss-of-function mutations and ankyrin-B deficiency vs. Normal ANK2/ankyrin-B expression was evaluated on Atrial electrophysiological dysfunction and susceptibility to AF. Ankyrin-B deficiency and loss-of-function mutations in ANK2 are associated with early-onset atrial fibrillation through decreased Cav1.3 channel membrane targeting and function.