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 ions are central to the cardiac excitability and contractility, and disturbances in calcium handling are a hallmark of many heart diseases. Among the downstream effectors, small conductance Ca 2+ -activated potassium (SK, K Ca 2) channels play a critical role in cardiac excitability and have attracted a growing interest for their contribution to both atrial and ventricular arrhythmogenesis. SK channels require calmodulin (CaM), a ubiquitous intracellular Ca 2+ sensor, as an obligatory interacting protein. SK channel and CaM provide the direct link between beat-to-beat changes in intracellular Ca 2+ concentration and cardiac membrane potentials. Importantly, human genetic studies have identified heritable CaM mutations that are linked to calmodulinopathy, human arrhythmia syndromes associated with SCD. Since CaM regulates multiple cardiac ion channels, it is unclear how individual CaM mutations affect SK channel function and arrhythmia susceptibility. To address this, we first employed computational studies to determine the differential effects of distinct human CaM mutations on SK channel function. We then tested the results in murine knockin models carrying F90L and N54I CaM variants. Using in vivo phenotyping, in vitro analyses of isolated ventricular myocytes, as well as ex vivo experiments, both camodulinopathy models alter the cardiac β-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.
Zheng et al. (2026) studied this question.