Abstract 13900: Secretoneurin is an Endogenous CaMKII Inhibitor That Attenuates Ca2+-Dependent Arrhythmogenesis

Introduction: Circulating secretoneurin (SN) levels are reported to predict mortality in patients with myocardial dysfunction. SN has also been observed to inhibit Ca2+/calmodulin-dependent protein kinase II δ (CaMKIIδ) activity. Objectives: To investigate the mechanism by which SN inhibits CaMKIIδ activity, and whether elevation of SN protects against Ca2+-dependent arrhythmia. Methods and Results: Using pull down experiments and structural homology modeling, SN binding was mapped to the substrate binding site in the catalytic region of CaMKIIδ. SN attenuated isoproterenol (ISO)-induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts, and inhibited CaMKIIδ-dependent ryanodine receptor 2 (RyR2) phosphorylation. SN was also observed to decrease RyR2 open probability in lipid bilayer experiments. In line with CaMKIIδ and RyR2 inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during ISO challenge. Ca2+ wave frequency was reduced, which corresponded with lowe...