Cacna2d3-KO Mouse

Cacna2d3, an auxiliary member of the alpha-2/delta subunit three family of the voltage-dependent calcium channel complex, plays crucial roles in multiple biological processes [2]. It is involved in regulating calcium channels, which are essential for processes like synaptic transmission, cellular excitability, and signal transduction [6,7].

Loss-of-function studies have provided significant insights into Cacna2d3's role. In PV-expressing neurons, knockout of Cacna2d3 (PVCre;Cacna2d3f/f mice) led to autistic-like phenotypes, including impaired sociability, increased repetitive behavior, and anxiety-like behavior, along with improved spatial memory. This was accompanied by reduced GAD67 and PV expression in the mPFC, increasing neuronal excitability and contributing to abnormal social behavior [1]. In zebrafish, mutant alleles of cacna2d3 caused reduced habituation of the acoustic startle response and increased startle sensitivity to acoustic stimuli, indicating its role in sensory filtering [3]. In cancer research, downregulation of CACNA2D3 was detected in gliomas, esophageal squamous cell carcinoma, and endometrial cancer. Overexpression of CACNA2D3 in these cancer cells inhibited cell proliferation, migration, invasion, and enhanced chemosensitivity, often through mechanisms like calcium-mediated apoptosis and suppression of pathways such as PI3K/Akt [2,4,5]. In myocardial ischemia-reperfusion injury, remote ischemic preconditioning reduced the expression of Cacna2d3, inhibiting calpain 1 activation and subsequent apoptosis [6].

In conclusion, Cacna2d3 is vital for normal physiological functions, especially those related to the nervous system and calcium-mediated cellular processes. Gene knockout models, especially in mice, have been instrumental in revealing its role in autism-like phenotypes and in various cancer types. These findings contribute to understanding the pathogenesis of these diseases and may potentially lead to new therapeutic strategies.

References:

1. Shao, Wei, Zheng, Hang, Zhu, Jingwen, Wang, Kai, Jiang, Xiao. 2023. Deletions of Cacna2d3 in parvalbumin-expressing neurons leads to autistic-like phenotypes in mice. In Neurochemistry international, 169, 105569. doi:10.1016/j.neuint.2023.105569. https://pubmed.ncbi.nlm.nih.gov/37419212/

2. Jin, Yi, Cui, Daming, Ren, Jie, Zeng, Tao, Gao, Liang. 2016. CACNA2D3 is downregulated in gliomas and functions as a tumor suppressor. In Molecular carcinogenesis, 56, 945-959. doi:10.1002/mc.22548. https://pubmed.ncbi.nlm.nih.gov/27583705/

3. Santistevan, Nicholas J, Nelson, Jessica C, Ortiz, Elelbin A, Granato, Michael, Grinblat, Yevgenya. 2022. cacna2d3, a voltage-gated calcium channel subunit, functions in vertebrate habituation learning and the startle sensitivity threshold. In PloS one, 17, e0270903. doi:10.1371/journal.pone.0270903. https://pubmed.ncbi.nlm.nih.gov/35834485/

4. Nie, Changjun, Qin, Xiaohui, Li, Xiaoyan, Hong, An, Chen, Xiaojia. 2019. CACNA2D3 Enhances the Chemosensitivity of Esophageal Squamous Cell Carcinoma to Cisplatin via Inducing Ca2+-Mediated Apoptosis and Suppressing PI3K/Akt Pathways. In Frontiers in oncology, 9, 185. doi:10.3389/fonc.2019.00185. https://pubmed.ncbi.nlm.nih.gov/31001468/

5. Kong, Xiangnan, Li, Min, Shao, Kai, Wang, Qian, Cai, Meijuan. 2019. Progesterone induces cell apoptosis via the CACNA2D3/Ca2+/p38 MAPK pathway in endometrial cancer. In Oncology reports, 43, 121-132. doi:10.3892/or.2019.7396. https://pubmed.ncbi.nlm.nih.gov/31746409/

6. Liu, Guoyang, Lv, Yong, Wang, Yanting, Li, Xia, Wu, Qingping. 2023. Remote ischemic preconditioning reduces mitochondrial apoptosis mediated by calpain 1 activation in myocardial ischemia-reperfusion injury through calcium channel subunit Cacna2d3. In Free radical biology & medicine, 212, 80-93. doi:10.1016/j.freeradbiomed.2023.12.030. https://pubmed.ncbi.nlm.nih.gov/38151212/

7. Wadle, Simon L, Schmitt, Tatjana T X, Engel, Jutta, Kurt, Simone, Hirtz, Jan J. 2022. Altered population activity and local tuning heterogeneity in auditory cortex of Cacna2d3-deficient mice. In Biological chemistry, 404, 607-617. doi:10.1515/hsz-2022-0269. https://pubmed.ncbi.nlm.nih.gov/36342370/