Calcium-Activated Chloride Channels: Linking Chloride Homeostasis and Calcium Signaling to Neuronal Excitability and Disease

Calcium-activated chloride channels (CaCCs) are increasingly recognized as critical regulators of neuronal excitability, synaptic integration, sensory transduction, and ionic plasticity throughout the nervous system. Acting at the interface between intracellular calcium signaling and chloride homeostasis, CaCCs couple activity-dependent calcium elevations to dynamic changes in membrane excitability. Unlike canonical cationic conductances, the physiological effects of CaCC activation are not intrinsically excitatory or inhibitory but instead depend dynamically on intracellular chloride concentration and local chloride driving force. This state dependence allows CaCCs to function as chloride-sensitive calcium effectors whose polarity varies across neuronal populations, developmental stages, and pathological conditions. Recent advances in structural biology, electrophysiology, chloride imaging, and transcriptomics have substantially expanded current understanding of TMEM16/anoctamin channels, particularly TMEM16A and TMEM16B, revealing complex interactions among calcium binding, membrane voltage, phospholipid signaling, and ionic microdomains. In mature central neurons characterized by low intracellular chloride concentrations, CaCC activation frequently contributes to activity-dependent inhibitory feedback and dendritic stabilization. Conversely, in sensory neurons, immature circuits, and disease states associated with chloride accumulation, identical conductances may amplify depolarization and facilitate pathological hyperexcitability. This review summarizes the molecular organization, regional distribution, physiological functions, and pathological implications of neuronal CaCCs, with particular emphasis on how chloride homeostasis dynamically determines the functional polarity of calcium-dependent chloride signaling.