Defining the role of KCNN1 in atrial arrhythmias

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Atrial fibrillation (AF) is the most prevalent form of cardiac arrhythmia affecting up to 2% of population and with an estimated individual lifetime risk of 25%-30%. AF is associated with a significant reduction in quality of life and increased morbidity and mortality. Frontline therapies such as beta blockers and Ca2+ channels blockers help control cardiac rhythm to reduce the symptoms, but do not prevent AF. Therefore the discovery of atria- specific targets to treat AF is imperative. Recently, small conductance Ca2+ activated K+ (SK) channels have emerged as a plausible atria-specific anti-arrhythmic target, given their limited functional roles in ventricular cardiomyocytes from healthy hearts. All three SK channels isoforms (SK1-3) are expressed both in atria and ventricles. However, the therapeutic potential of SK2 and SK3 remains highly controversial, given both loss- and gain-of-function of these channels were linked to increased atrial arrhythmogenesis in various genetic mouse models and in GWAS association studies. Furthermore, recent reports demonstrated SK current in ventricular myocytes from diseased or stressed hearts, revealed to play a protective role in reducing Ca2+-dependent arrhythmia-triggering events. Importantly, our previously published data showed no discernible role of SK1 (KCNN1) in ventricular protection, unlike SK2 and SK3. Based on this knowledge, and the fact that SK1 is the only isoform with 2-5 fold higher expression in atria vs ventricles, we posit that SK1 can be a bona fide atria- specific antiarrhythmic target, unlike SK2 and SK3. Accordingly, the major goal of this proposal is to establish the roles of SK1 in normal atrial myocytes (AMs) and AMs from the hearts with AF. Abnormally high activity of sarcoplasmic reticulum (SR) Ca2+ release channel complex, the ryanodine receptor (RyR2), is thought to underlie arrhythmia trigger for AF. Therefore, to test SK1 antiarrhythmic potential, we will use the well-established mouse model of RyR2 complex gain-of function caused by calsequestrin (CASQ2) knockout, a SR protein that determines controls RyR2 activity and SR Ca2+ storage capacity. To explore the functional consequences of gain- and loss-of-SK1 channel function, we propose to generate new cardiac-specific SK1 overexpression and KO mouse lines. Importantly, SK1 might be expressed in the mitochondrial inner membrane in addition to the sarcolemma. We hypothesize that facilitating sarcolemmal SK1 channel function may substantially diminish pro- arrhythmic early and delayed afterdepolarizations (EADs and DADs respectively) by countering the depolarizing force of L-type Ca2+ channels and Na+/Ca2+ exchanger, thus reducing triggered activity. We posit that mito-SK1 channel activation can further attenuate pro-arrhythmic Ca2+-dependent DADs and EADs by reducing excessive production of damaging reactive oxygen species, thereby improving disturbed RyR2 complex-mediated SR Ca2+ release in diseased AMs. We anticipate our work will validate SK1 as a novel atria-specific antiarrhythmic target.