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

Abstract

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over two million patients in the US 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 Here, 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 (Cav1.3) responsible for low-voltage activated L-type Ca2+current. Ankyrin-B directly associates with Cav1.3, and this interaction is regulated by a short, highly-conserved motif specific to Cav1.3. 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 atrial fibrillation. Additionally, our data demonstrate a novel pathway for ankyrin-B-dependent regulation of Cav1.3 channel membrane targeting and regulation in atrial myocytes.

G protein-gated I KACh channels as therapeutic targets for treatment of sick sinus syndrome and heart block

“…Indeed, Ca v 1.3 −/− mice present several aspects of human SSS (10,18), including SAN dysfunction (1, 2) and tachycardia-bradycardia syndrome (33,34). In addition, Ca v 1.3 −/− mice reproduce severe AV dysfunction typical of human congenital heart block (16).…”

Regulation of Gene Transcription by Voltage-gated L-type Calcium Channel, Cav1.3

“…These observations were surprising, yet insightful as they suggest that detailed knowledge of the different Ca 2ϩ channel isoforms may have broad therapeutic ramifications in the treatment of atrial arrhythmias. Indeed, recent studies have confirmed the expression and critical roles of the Ca v 1.3 isoform in the human heart (6), and Ca v 1.3 as a possible link between ankyrin-B mutations and early onset atrial fibrillation in patients (7).…”

Ankyrin-B Protein in Heart Failure

“…Thus, due to its multiple roles in cardiac structural and electrical regulation, alterations in ankyrin-B levels in either acute or chronic cardiac injury appear particularly detrimental to heart function and physiology. Notably, these predictions are supported in the literature by multiple forms of rare monogenic cardiovascular disease that target ankyrin-B, resulting in increased susceptibility to sinus node disease, atrial fibrillation, and ventricular tachycardia (11,15,28).…”

“…Failure-Despite direct links between ankyrin-B (ANK2) loss-of-function mutations and human arrhythmia phenotypes (sinus node disease, atrial fibrillation, ventricular arrhythmia) (11,12,15), there are no data related to ankyrin-B regulation in acquired human cardiovascular disease. We therefore examined ankyrin-B expression levels in human heart failure samples.…”

“…Dysfunction in the ankyrin-G pathway is linked with human Brugada syndrome arrhythmia (7)(8)(9)(10). Human mutations in a second cardiac ankyrin gene product, ankyrin-B, are directly linked with sinus node dysfunction, atrial fibrillation, ventricular tachycardia following catecholaminergic stress, and susceptibility to sudden cardiac death (11)(12)(13)(14)(15). Moreover, ANK2 (encodes ankyrin-B) gene variants are linked with rate corrected QT interval variation in large patient populations (16).…”