Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome

作者：Wolf Roseanne M; Mitchell Colleen C; Christensen Matthew D; Mohler Peter J; Hund Thomas J^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2010, 299(5): H1505-H1514.

DOI：10.1152/ajpheart.00503.2010

• Na+/Ca2+ exchanger
• Na+-K+-ATPase
• mathematical model
• trafficking
• calcium

Wolf RM, Mitchell CC, Christensen MD, Mohler PJ, Hund TJ. Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome. Am J Physiol Heart Circ Physiol 299: H1505-H1514, 2010. First published August 20, 2010; doi: 10.1152/ajpheart.00503.2010.-Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been linked to human cardiac arrhythmia. More recently, defects in ion channel-associated proteins have been associated with arrhythmia. Ankyrin-B is a multifunctional adapter protein responsible for targeting select ion channels, transporters, cytoskeletal proteins, and signaling molecules in excitable cells, including neurons, pancreatic beta-cells, and cardiomyocytes. Ankyrin-B dysfunction has been linked to cardiac arrhythmia in human patients and ankyrin-B heterozygous (ankyrin-B+/-) mice with a phenotype characterized by sinus node dysfunction, susceptibility to ventricular arrhythmias, and sudden death ("ankyrin-B syndrome"). At the cellular level, ankyrin-B+/- cells have defects in the expression and membrane localization of the Na+/Ca2+ exchanger and Na+-K+-ATPase, Ca2+ overload, and frequent afterdepolarizations, which likely serve as triggers for lethal cardiac arrhythmias. Despite knowledge gathered from mouse models and human patients, the molecular mechanism responsible for cardiac arrhythmias in the setting of ankyrin-B dysfunction remains unclear. Here, we use mathematical modeling to provide new insights into the cellular pathways responsible for Ca2+ overload and afterdepolarizations in ankyrin-B+/- cells. We show that the Na+/Ca2+ exchanger and Na+-K+-ATPase play related, yet distinct, roles in intracellular Ca2+ accumulation, sarcoplasmic reticulum Ca2+ overload, and afterdepolarization generation in ankyrin-B+/- cells. These findings provide important insights into the molecular mechanisms underlying a human disease and are relevant for acquired human arrhythmia, where ankyrin-B dysfunction has recently been identified.

• 出版日期2010-11