Regulation of cardiac small-conductance calcium-activated potassium channels by PIP2

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PROJECT SUMMARY Cardiac arrhythmia is a condition where the heart’s electrical signals are disrupted, causing the heart to beat in an irregular and dyssynchronous manner. While some arrhythmias may be benign, others can be life- threatening, as the ability of the heart to perfuse the vital organs with oxygen and nutrients is severely compromised. Small conductance calcium-activated potassium channels (SK channels) are activated by the increase of intracellular calcium concentrations on a beat-to-beat basis. SK channels play critical roles in the regulation of cardiac excitability, and dysfunction of cardiac SK channels causes cardiac arrhythmias including atrial fibrillation (AF). Therefore, SK channel may represent a novel therapeutic target for cardiac arrhythmias. The regulation mechanisms of cardiac SK channels have been extensively studied. Phosphatidylinositol 4,5- bisphosphate (PIP2) is an essential regulator of many plasma membrane-bound proteins, including cardiac ion channels. Hence, PIP2 may play critical roles in arrhythmia initiation and maintenance. However, whether and how cardiac SK channels are regulated by PIP2 are still unknown. We hypothesize that SK channels are regulated by PIP2 in cardiomyocytes and PIP2 plays a critical role in the trafficking of SK channels. To test the hypothesis, we will use multidisciplinary approaches including patch-clamp, total internal reflection fluorescence (TIRF) microscopy, super-resolution immunofluorescence imaging, optogenetics and genetic manipulations. Three specific aims are: (1) determine the regulation of SK channels by PIP2 using optogenetic techniques; (2) determine the molecular mechanisms of PIP2 regulation of SK channels; (3) test the physiological impact of PIP2 regulation in cardiomyocytes. These studies will reveal a new regulatory mechanism of cardiac SK channels by PIP2. The anticipated results will provide novel insights into the functional role of SK channels and PIP2 signaling in the regulation of cardiac excitability and arrhythmia. At the translational level, cardiac SK channels may represent a potential therapeutic target for the treatment of cardiac arrhythmia.