Ankyrin-based targeting pathway regulates human sinoatrial node automaticity

Abstract

Cellular defects in ankyrin-based ion channels and transporter targeting pathways have previously been linked with abnormal vertebrate physiology and human disease. In a recent study, our group linked dysfunction in cardiac ankyrin-B function with human sinus node disease. Ankyrin-B deficient mice displayed bradycardia and heart rate variability similar to individuals harboring an ANK2 variant. Isolated sinoatrial node (SAN) cells from ankyrin-B-deficient animals displayed abnormal membrane expression of Na+/Ca2+ exchanger (NCX1), Na+/K+ ATPase (NKA), IP3 receptor (IP3R) and, surprisingly, Ca(V)1.3. Loss of ankyrin-B promoted slow and irregular Ca2+ release, as well as afterdepolarizations in isolated SAN cardiomyocytes. Our findings suggest that ankyrin-B serves as a critical focal point for channels and transporters important for sarcoplasmic reticulum (SR) calcium homeostasis as well as membrane depolarization in SAN cells. The severity and penetrance of human ANK2 sinus node dysfunction likely reflects the essential role of ankyrin-B for orchestrating membrane function of multiple SAN ion channel and transporters within a single functional pathway. Therefore, ankyrin-based pathways may serve as ideal therapeutic targets in SAN cardiomyocytes where a "multi-hit" approach is necessary to impact a complex process such as SAN cell automaticity. In summary, our new findings define a novel genetic basis for human SND and expand our understanding of the critical role that ankyrin-based targeting pathways play in excitable cell physiology.