Calhm2, or calcium homeostasis modulator family protein 2, has diverse functions. It is involved in processes like calcium regulation, which is crucial for various cellular functions. It also plays a role in purinergic signaling through ATP release and is associated with mitochondrial protein import and fatty acid metabolism [3,5,6].

In AD mouse models (5×FAD mice), both conventional and conditional microglial knockout of Calhm2 reduced amyloid β deposition, neuroinflammation, and cognitive impairments, highlighting its role in microglial activation and AD pathology [1]. In PD models, conventional and microglial Calhm2 knockout decreased dopaminergic neuronal loss and improved locomotor performance by inhibiting EFHD2-STAT3 signaling in microglia [2]. In inflammation-related pain and anxiety models, knockdown of Calhm2 in the anterior cingulate cortex reversed pain behaviors and comorbid anxiety symptoms [4]. In depression-like behavior models, Calhm2 knockout in astrocytes led to reduced ATP levels, neural dysfunction, and depression-like behaviors, which were rescued by ATP replenishment [5].

In conclusion, Calhm2 is a multifunctional protein involved in important biological processes. Gene knockout and knockdown studies in mouse models have revealed its significance in neurodegenerative diseases such as AD and PD, as well as in inflammation-related pain, anxiety, and depression-like behaviors, providing potential therapeutic targets for these conditions.

References:

1. Cheng, Jinbo, Dong, Yuan, Ma, Jun, Yu, Ye, Yuan, Zengqiang. 2021. Microglial Calhm2 regulates neuroinflammation and contributes to Alzheimer's disease pathology. In Science advances, 7, . doi:10.1126/sciadv.abe3600. https://pubmed.ncbi.nlm.nih.gov/34433553/

2. Bo, Xuena, Xie, Fei, Zhang, Jingdan, Yuan, Zengqiang, Cheng, Jinbo. 2023. Deletion of Calhm2 alleviates MPTP-induced Parkinson's disease pathology by inhibiting EFHD2-STAT3 signaling in microglia. In Theranostics, 13, 1809-1822. doi:10.7150/thno.83082. https://pubmed.ncbi.nlm.nih.gov/37064868/

3. Jonas, Elizabeth, Mnatsakanyan, Nelli, Rivera-Molina, Felix, Caplan, Michael, Khokha, Mustafa. 2024. CALHM2 is a mitochondrial protein import channel that regulates fatty acid metabolism. In Research square, , . doi:10.21203/rs.3.rs-4985689/v1. https://pubmed.ncbi.nlm.nih.gov/39315269/

4. Li, Xiaohui, Xiong, Mengyuan, Gao, Yan, Xu, Xueqin, Ke, Changbin. 2023. Upregulation of Calhm2 in the anterior cingulate cortex contributes to the maintenance of bilateral mechanical allodynia and comorbid anxiety symptoms in inflammatory pain conditions. In Brain research bulletin, 204, 110808. doi:10.1016/j.brainresbull.2023.110808. https://pubmed.ncbi.nlm.nih.gov/37926398/

5. Ma, J, Qi, X, Yang, C, Zhang, C, Yuan, Z. 2017. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. In Molecular psychiatry, 23, 883-891. doi:10.1038/mp.2017.229. https://pubmed.ncbi.nlm.nih.gov/29180673/

6. Choi, Si Won, Kwon, Jae-Won, Kang, Tong Mook, Park, Kyoung Sun, Kim, Sung Joon. 2024. Calcium homeostasis modulator 2 (Calhm2) as slowly activating membrane current channel in mouse B cells. In Biochemical and biophysical research communications, 699, 149561. doi:10.1016/j.bbrc.2024.149561. https://pubmed.ncbi.nlm.nih.gov/38280307/