CLC2

ClC-2, or chloride channel CLC-2, is a member of the CLC family of chloride channels. In humans it is encoded by the CLCN2 gene. ClC-2 forms a voltage-gated, chloride-selective channel that functions as a dimer, with each subunit contributing to a single pore. It is widely expressed, with notable levels in the brain, kidney, intestine, and other tissues.

Physiological role: The channel mediates passive transport of Cl− ions across cell membranes and participates in regulating cell volume, transepithelial chloride transport, and the resting membrane potential of certain cells. In epithelia, ClC-2 supports Cl− movement across tight junctions, contributing to fluid balance. In the central nervous system, expression in glial cells is thought to help maintain extracellular ionic conditions that influence neuronal activity.

Regulation and biophysics: ClC-2 is activated by membrane hyperpolarization and may respond to cell swelling and intracellular pH changes. It belongs to the CLC family’s gating mechanisms and displays voltage-dependent behavior that favors inward Cl− flow under hyperpolarized conditions.

Clinical relevance: Pathogenic variants in CLCN2 have been associated with hereditary leukodystrophy and other neurological disorders, including seizures in some cases, though the spectrum and mechanisms are still under investigation. Animal and cellular studies continue to clarify its role in volume regulation and chloride homeostasis in health and disease.