KCNN2 encodes a small-conductance calcium-activated potassium channel (SK2/KCa2.2) that mediates voltage-independent potassium transport across cell membranes through constitutive binding with calmodulin, which gates the channel upon intracellular calcium elevation. The channel exhibits inward rectification, reducing outward potassium conductance particularly at positive membrane potentials, and plays a critical role in the repolarization phase of cardiac action potentials and neuronal excitability. Pathogenic KCNN2 variants cause autosomal dominant neurodevelopmental and movement disorders. De novo and inherited loss-of-function variants lead to intellectual disability, cerebellar ataxia, dystonia, and myoclonus 1, with heterozygous mutations demonstrating dominant-negative effects on channel function 2. In cardiac contexts, common KCNN2 polymorphisms associate with increased risk for ventricular tachyarrhythmias and sudden cardiac death 3, while KCNN2/KCNN3 downregulation occurs in atrial fibrillation with heart failure 4. Recent structural insights reveal the channel's selectivity filter architecture and drug-binding modes 5. Pharmacologically, SK2 inhibition by nitrous oxide contributes to rapid antidepressant effects via layer V prefrontal cortex activation 6, while SK2 activity regulates migration and chemosensitivity in ovarian cancer, suggesting dual therapeutic potential as activators to enhance chemotherapy or inhibitors to limit metastatic spread 7.