CALHM2 is a pore-forming subunit of calcium homeostasis modulator channels that mediates ATP release from astrocytes and ATP-induced calcium influx in microglia 1. The protein forms large-pore channels with variable oligomeric assemblies—human CALHM2 characteristically assembles as undecamers—with the N-terminal helix modulating the channel pore and ATP conductance 2. CALHM2 regulates neuronal ATP and calcium homeostasis, synaptic transmission, and neuroinflammatory responses, and can form heteromeric channels with other CALHM paralogs 3. CLINICAL SIGNIFICANCE: The CALHM2 V136G polymorphism (rs232660) is significantly associated with Alzheimer's disease risk and depression, as this mutation impairs ATP-release function in astrocytes and synaptic plasticity 1. In Parkinson's disease, CALHM2 aggravates α-synuclein-induced neurotoxicity through PARP-1-dependent parthanatos, and CALHM2 knockdown mitigates this pathology 4. Conversely, CALHM2 knockout enhances natural killer cell cytotoxicity and cytokine production, improving CAR-NK cell-based cancer immunotherapy efficacy in resistant tumors 5. CALHM2 represents a therapeutic target: neurotropin alleviates Alzheimer's pathology by suppressing FUS-mediated CALHM2 transcription and blocking CALHM2-EFhd2 interaction, restoring mitochondrial function and microglial polarization 6. Calcium dysregulation involving CALHM2 contributes to multiple AD pathologies including neuroinflammation, oxidative stress, and mitochondrial dysfunction 7.