KCNK9 encodes TASK-3, a two-pore domain potassium channel that conducts voltage-dependent outward rectifying currents through an ion-flux gating mechanism where outward potassium flow opens the gate. The channel exhibits pH sensitivity, becoming permeable to sodium ions upon extracellular acidification through protonation of a histidine residue that stabilizes channel inactivation. KCNK9 is maternally expressed through genomic imprinting and forms functional homo- and heterodimeric channels with distinct regulatory properties. In the central nervous system, KCNK9 regulates neuronal excitability by hyperpolarizing resting membrane potential in cerebellar and hippocampal granule neurons, while also supporting high-frequency action potential firing. The channel mediates pH-sensitive currents in serotonergic raphe neurons and regulates retinal ganglion cell firing, contributing to visual information transmission. In the adrenal gland, KCNK9 maintains hyperpolarization of aldosterone-producing cells and limits aldosterone release. Pathogenic KCNK9 variants cause KCNK9 imprinting syndrome (KIS), a neurodevelopmental disorder characterized by motor and speech delay, intellectual disability, feeding difficulties, hypotonia, and dysmorphic features 1. Disease-causing variants exhibit variable functional effects including gain and loss of channel conductance, with consistent loss of channel regulation 1. KCNK9 is also amplified and overexpressed in 44% of breast cancers, where overexpression promotes tumor formation and confers resistance to hypoxia and serum deprivation 2. Monoclonal antibodies targeting KCNK9's extracellular domain inhibit lung cancer xenograft growth and breast cancer metastasis 3. Doxapram, an FDA-approved respiratory stimulant, functions as a potent inhibitor of human KCNK9 channels 4.