ClC3

ClC3, short for chloride intracellular channel 3, is a member of the CLC family of chloride channels and transporters. In humans, it is encoded by the CLCN3 gene. The protein is predominantly localized to intracellular organelles, especially late endosomes and lysosomes, with some neuronal populations showing localization to synaptic vesicles. It is generally described as a Cl-/H+ exchanger rather than a classical plasma membrane chloride channel, although its exact transport mode may vary by cellular context. Through exchanging chloride and protons across endolysosomal membranes, ClC3 helps regulate organelle pH, ionic strength, and volume, thereby influencing endosomal trafficking, receptor recycling, and cargo processing.

ClC3 expression is widespread, with notable abundance in the brain, heart, and immune tissues. In neurons, ClC3 contributes to intracellular chloride homeostasis within vesicular compartments, potentially affecting synaptic function and dendritic spine morphology, as part of vesicle acidification and trafficking processes.

Regulation of ClC3 involves phosphorylation and protein interactions; cellular stress and osmotic changes can modify its activity. In animal models, genetic deletion of ClC3 leads to impaired endolysosomal function and neurodevelopmental or neurodegenerative phenotypes, with increased susceptibility to seizures, underscoring a role in neuronal homeostasis.

Clinical relevance remains an active area of study. Altered ClC3 expression or function has been reported in certain neurological disorders and cancers in experimental settings, but no common human disease is linked to CLCN3 mutations at present.