KCNK4 encodes a two-pore-domain potassium channel that functions as a mechanosensitive and thermosensitive leak channel 1. The channel operates in two modes: voltage-dependent outward rectification under resting conditions, and voltage-independent leak conductance upon stimulation by mechanical stretch, pH changes, heat, and lipids 2. KCNK4 heterodimerizes with other K2P channels, particularly KCNK2/TREK-1, to form channels with distinct regulatory properties that facilitate rapid repolarization and high-speed saltatory conduction in myelinated sensory nerves 1. The channel is widely expressed in nervous tissue, brain, heart, and periodontal ligaments 3. Gain-of-function variants in KCNK4 cause FHEIG syndrome (facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth) 24. Patch-clamp analyses show these mutations increase basal channel activity and impair sensitivity to mechanical stimulation and arachidonic acid 2. Molecular dynamics simulations indicate mutations favor sealing of lateral intramembrane fenestrations, enhancing potassium flow 2. De novo variants cluster in regions critical for channel conformation, while variants in less critical domains may cause milder phenotypes like isolated Rolandic epilepsy 4. KCNK4 has also been identified as a bipolar disorder risk gene through fine-mapping studies 5, and upregulation of KCNK4 enhances chemosensitivity in ovarian cancer cells 6.