ABSTRACT Our laboratory was the first to demonstrate unequivocally that several isoforms of small conductance Ca2+- activated K+ channels (SK or KCa2 channels) underlie Ca2+-activated K+ current (IK,Ca) in cardiomyocytes. Since our original reports, knowledge of cardiac SK channels in the field has been greatly expanded. Studies by our group and more recently by others, have provided evidence to substantiate the important roles of SK channels in the heart. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human arrhythmias and atrial fibrillation (AF). Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Moreover, SK channels are upregulated in heart failure (HF). To our knowledge, they are the only K+ channels that are upregulated in HF, underpinning the importance of this class of channels in normal and diseased hearts. Significant gaps in our knowledge and seemingly contradictory findings on SK channel function in cardiac disease mechanisms are our motivations for the next grant cycle. These are the challenges: 1) Blockade of SK channels has been shown to be both anti-arrhythmic and proarrhythmic in various models; and 2) SK channels are upregulated in HF. However, the mechanisms for the observed upregulation remain incompletely understood. Thus, this multidisciplinary proposal will combine experimental and computational studies, taking advantage of complementary expertise from four different laboratories in functional studies, optogenetic tools, and computational modeling to successively address the multifaceted SK channel remodeling in diseased hearts. SK current is enhanced during -adrenergic (-AR) stimulation, especially in female animals, therefore, the sex-specific roles of SK channels will be tested. The proposed study represents the necessary and critical steps to disentangle the highly complex and sex-specific SK channel remodeling in HF, the unique K+ channel that helps to compensate for the much-needed “repolarization reserve” in HF.