KCNK3 encodes a two-pore domain potassium channel that conducts voltage-dependent outward rectifying K+ currents through an 'ion flux gating' mechanism where outward ion flow opens the channel gate 123. The channel exhibits pH sensitivity, becoming permeable to Na+ ions upon extracellular acidification through protonation of His-98, which stabilizes C-type inactivation 4. KCNK3 forms functional homo- and heteromeric channels with distinct regulatory properties and supports fast-gating kinetics critical for action potential repolarization 13. In the pulmonary circulation, KCNK3 regulates vascular smooth muscle membrane potential and is physiologically important for maintaining pulmonary vascular homeostasis 5. Loss-of-function KCNK3 variants cause pulmonary arterial hypertension (PAH), an autosomal dominant condition with incomplete penetrance, representing the first identified channelopathy in PAH 67. KCNK3 has definitive evidence for PAH causality and is recommended for genetic testing in PAH patients 8. KCNK3 dysfunction also contributes to dasatinib-associated PAH by decreasing K+ channel function, promoting mitochondrial dysfunction and endothelial cell dysfunction in pulmonary vessels 9. Genetic variants in KCNK3 account for approximately 2.7% of PAH cases and represent potential targets for biomarker development and therapeutic intervention 7.