Calhm2, or calcium homeostasis modulator family protein 2, is involved in multiple biological functions. It has been linked to processes like mitochondrial protein import, regulating fatty acid metabolism as it serves as the import channel for the ECHA subunit of the mitochondrial trifunctional protein [4]. It is also associated with extracellular ATP release, which is crucial for cell-to-cell signaling in the brain [7].

In various disease-related studies using knockout (KO) mouse models, Calhm2 has shown significant impacts. In Alzheimer's disease (AD) 5×FAD mice, both conventional and conditional microglial knockout of Calhm2 reduced amyloid β deposition, neuroinflammation, and cognitive impairments by inhibiting microglial pro-inflammatory activity and increasing phagocytic activity [1]. In Parkinson's disease (PD) model mice, conventional and microglial Calhm2 knockout decreased dopaminergic neuronal loss and microglial numbers, improving locomotor performance by inhibiting EFHD2-STAT3 signaling in microglia [3]. In models of depressive-like behaviors, conventional and conditional astrocyte knockout of Calhm2 led to reduced ATP concentrations, neural dysfunction, and depression-like behaviors, which could be rescued by ATP replenishment [7]. Also, the CALHM2 V136G mutation in a mouse model was associated with depressive-like behaviors and cognitive decline in old age, with the mutation causing loss of CALHM2 ATP-release function in astrocytes [2]. In addition, in a chronic inflammation pain model, knockdown of Calhm2 in the anterior cingulate cortex reversed pain behaviors and comorbid anxiety symptoms [6]. For NK cell-based immunotherapies, CALHM2-knockout NK cells showed enhanced cytotoxicity and tumor infiltration in mouse primary NK cells and human chimeric antigen receptor (CAR)-NK cells [5,8].

In conclusion, Calhm2 plays essential roles in multiple biological processes and is involved in various disease conditions. Studies using KO and conditional knockout mouse models have revealed its significance in microglial activation, neurodegenerative diseases like AD and PD, mood-related disorders, pain-related anxiety, and NK cell-based immunotherapies, providing potential therapeutic targets for these diseases.