CLCN2 encodes a voltage-gated, osmosensitive chloride channel that functions as a homodimeric channel with independent ion conduction pathways per subunit, controlled by fast glutamate gates and a slow common gate 123456. In neurons, CLCN2 contributes significantly to resting membrane conductance and prevents chloride accumulation in dendrites during GABAergic signaling 3. In glial cells, CLCN2 associates with HEPACAM/GlialCAM at astrocytic processes to buffer extracellular chloride and potassium, with astrocytic ClC-2 dysfunction impairing oligodendrocyte development through SPP1/CD44 signaling 7. CLCN2 regulates aldosterone biosynthesis in adrenal glomerulosa cells by controlling membrane depolarization and voltage-gated calcium channel activation 568. Loss-of-function CLCN2 mutations cause autosomal recessive leukoencephalopathy with ataxia, characterized by intramyelinic edema and white matter tract involvement 910. Somatic CLCN2 mutations contribute to approximately 10% of aldosterone-producing adenomas and familial hyperaldosteronism type 2 81112. Rare CLCN2 variants associate with familial epilepsy, though their pathogenic significance requires further investigation 13.