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

Article

关键词: CARDIAC-ARRHYTHMIA;    CALCIUM-CHANNELS;    MOLECULAR-BASIS;    DOWN-REGULATION;    ION-CHANNEL;    TRAFFICKING;    MECHANISMS;    EXPRESSION;    MUTATIONS;    INSIGHTS;   

DOI  :  10.1161/CIRCULATIONAHA.111.023986

来源: SCIE

【 摘 要 】

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 Ca2+ channels (Ca(v)1.3) responsible for low voltage-activated L-type Ca2+ 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. (Circulation. 2011;124:1212-1222.)

【 授权许可】

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