ANO4 (anoctamin 4) is a calcium-activated ion channel with dual functional properties, though its primary mechanisms remain partially divergent from other anoctamins. ANO4 functions as a Ca2+-dependent, non-selective monovalent cation channel with weak selectivity for K+ > Na+ > Li+ 1, with expression particularly enriched in the central nervous system and endocrine tissues 2. Beyond ion channel activity, ANO4 exhibits calcium-dependent phospholipid scramblase activity, facilitating phosphatidylserine externalization 3, though it generates low levels of calcium-activated chloride transport compared to ANO1 2. Mechanistically, ANO4 regulates glucose homeostasis through activation of glucose-inhibited neurons in the ventromedial hypothalamus during hypoglycemia, with genetic disruption impairing counterregulatory responses 4. ANO4 also modulates intracellular calcium signaling by colocalizing with SERCA pumps and ORAI-1 channels, promoting store-operated calcium entry 5. Clinically, ANO4 variants cause fever-sensitive developmental and epileptic encephalopathy (DEE), epileptic encephalopathy (EE), and generalized epilepsy with febrile seizures plus (GEFS+) through dominant-negative effects 6. Pathogenic missense variants impair protein stability and plasma membrane trafficking, reducing ion channel function and increasing apoptosis markers 6. ANO4 also regulates aldosterone secretion in the adrenal zona glomerulosa, where it attenuates stimulated secretion and cell proliferation 2.