Regulation and dysregulation of sodium channels by by calmodulin

Project Summary Sudden cardiac death is a leading cause of mortality in the United States and often results from cardiac arrhythmias. Mutations in Na+ channels, particularly in their carboxy terminal domains (CTDs), dysregulate beat- to-beat cycling of Na+ and Ca2+, and thereby, precipitate arrhythmias. Similarly, mutations in calmodulin (CaM), which closely regulates these channels, are also linked to arrhythmias. However, the role of Na+ channels in arrhythmogenesis remains unclear. NavCTD mutations, which alter the affinity of Nav CaM, impair fast inactivation and induce proarrhythmic late Nav current (INa). This particularly is evident for Nav isoforms which exhibits the lowest CaM affinity and correspondingly, the largest of late INa magnitude relative to peak INa. Our recent studies indicate an important role for these Nav isoforms in late INa-mediated arrhythmias. However, the arrhythmogenic impact of Nav dysregulation in calmodulin-driven arrhythmias remains unclear. Based on strong preliminary data from our laboratory, we hypothesize that affinity of CaM for Nav will dictate the magnitude of arrhythmogenic late INa. Diminished CaM binding to the NavCTD will increase late INa, while enhanced binding will hasten channel inactivation, mitigating proarrhythmic late INa. Thus, we propose to: 1) Assess the extent and mechanism of NaV dysregulation by CaM. 2) Elucidate the relative contribution of mutant CaM-mediated Nav dysfunction to calmodulinopathy associated arrhythmias. 3) Examine the antiarrhythmic potential of enhancing CaM-Nav interaction. Thus, by understanding calmodulinopathies, we aim to discover approaches to prevent arrhythmias stemming from both aberrant CaM-NaV interaction and abnormal NaV function.