Atrial fibrillation (AF) is the most common sustained arrhythmia clinically. There are accumulating evidence to suggest that ion channel modulation and remodeling play a significant role in the maintenance of AF. A variety of ionic channel abnormalities have been reported in atrial myocytes from patients and animal models with AF. Importantly, a decrease in Ca2+ current density by ~70% in atrial myocytes of patients with persistent AF has been reported. We have obtained recent evidence to demonstrate that several isoforms of small conductance Ca2+- activated K+ channels (SK or KCa2 channels) are expressed and play important roles in the repolarization of human atrial myocytes. Moreover, we have obtained new evidence to support the functional crosstalk between Ca2+ and SK channels. Hence, the goal of the proposal is test the functional coupling between SK and Cav1.3 channels at multiple levels in three independent yet mechanistically linked Aims. The critical roles of these subclasses of KCa channels in human atrial myocytes are only beginning to emerge. Very little is known regarding the regulations of SK channels in the heart. Moreover, mechanistic data from human heart remains extremely limited. Indeed, novel insights into atrial-specific ion channels may provide new treatment paradigms to target these channels without interfering with the excitability of ventricular tissues. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common sustained arrhythmia clinically. The essence of this proposal is to deploy innovative biochemical, molecular, imaging and functional analyses to test the functional interaction between Ca2+ and SK channels in human atrial myocytes. Novel insights into atrial-specific ion channels may provide new treatment paradigms to target these channels without interfering with the excitability of ventricular tissues.