Abstract Body: Cardiac arrhythmias and heart failure pose a significant public health problem. Sudden cardiac death (SCD) is one of the leading causes of mortality worldwide. Calcium ion is essential to the cardiac electrophysiology and contractility, and calcium mishandling is a hallmark of heart diseases. The small conductance Ca²⁺-activated potassium (SK) channel plays a critical role in cardiac excitability and has gained increasing interest due to its involvement in both atrial and ventricular arrhythmogenesis. Calmodulin (CaM) is a ubiquitous intracellular calcium-sensing protein that serves as the obligatory SK channel interacting protein. SK channel and CaM provide the direct link between beat-to-beat changes in intracellular calcium concentration and cardiac membrane potentials. Recent studies have provided genetic links between human heritable CaM mutations, or calmodulinopathy, and cardiac arrhythmias and sudden cardiac death. Since CaM regulates a multitude of cardiac ion channels, we first utilize computational studies to determine the differential effects of distinct human CaM mutations on SK channel function. We take advantage of two CaM F90L and N54I knockin murine models to test our computational findings, using in vivo phenotyping and in vitro analyses in isolated ventricular myocytes. We found that both camodulinopathy models alter the cardiac beta-adrenergic responses. In addition, the arrhythmia inducibility is much higher in the F90L^+/- mice and the calcium transient was significant decreased in F90L^+/- compared to the WT animals. SK currents and channel expression are quantified from isolated cardiac myocytes in order to determine the critical roles of SK channels in the distinct phenotypes in human calmodulinopathy.