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

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.

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.