Cav3, also known as T-type, low-voltage activated calcium channels, play a crucial role in regulating neuronal excitability. They are involved in various physiological functions, especially in the nervous system, contributing to sensory processing, sleep, and hormone and neurotransmitter release [1]. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to neurodevelopmental, neurological, and psychiatric diseases [1].

In multiple disease models, Cav3.2 (a subtype of Cav3) shows significant impacts. In non-alcoholic fatty liver disease (NAFLD) mouse models, Cav3.2 knockout (KO) improved hepatic steatosis, liver injury, and metabolic syndrome, inhibited oxidative stress, inflammation, and hepatocyte apoptosis [2]. In a cerebral ischemia/reperfusion injury mouse model, Cav3.2 KO reduced infarct volume, brain water content, and alleviated neurological dysfunction, as well as attenuated oxidative stress, inflammatory response, and neuronal apoptosis [4]. In atopic dermatitis-like mouse models, Cav3.2 deficiency reduced histamine, IL-4/IL-13, and TSLP-induced itch, and genetic knockout or pharmacological inhibition decreased scratching behaviors and skin inflammation [3]. Cav3.2 null mice also exhibited decreased scratching responses in histamine-or chloroquine-induced acute itch models [5]. In the spinal cord lamina II neurons of mice, Cav3.2 ablation in the dorsal horn had drastic effects on neuron excitability, blunting transient firing patterns, rebound depolarizations, and remodeling action potential kinetics [6].

In conclusion, Cav3 channels, especially Cav3.2, are essential for normal physiological functions in the nervous system. The gene knockout mouse models have revealed their significant roles in various disease conditions such as NAFLD, cerebral ischemia/reperfusion injury, atopic dermatitis-related itch, and pain-related neuronal excitability in the spinal cord. These findings highlight the potential of targeting Cav3 channels for the treatment of related diseases.

References:

1. Lory, Philippe, Nicole, Sophie, Monteil, Arnaud. 2020. Neuronal Cav3 channelopathies: recent progress and perspectives. In Pflugers Archiv : European journal of physiology, 472, 831-844. doi:10.1007/s00424-020-02429-7. https://pubmed.ncbi.nlm.nih.gov/32638069/

2. Li, Xue, Hu, Chengyun, Luo, Shanshan, Jiang, Lai, Tang, Chaoliang. 2024. Cav3.2 deletion attenuates nonalcoholic fatty liver disease in mice. In Gene, 929, 148812. doi:10.1016/j.gene.2024.148812. https://pubmed.ncbi.nlm.nih.gov/39116959/

3. Ahn, Ji-Woong, Kim, Song-Ee, Kim, Do-Young, Chung, Seungsoo, Lee, Sang Eun. 2023. Cav3.2 T-Type Calcium Channel Mediates Acute Itch and Contributes to Chronic Itch and Inflammation in Experimental Atopic Dermatitis. In The Journal of investigative dermatology, 144, 612-620.e6. doi:10.1016/j.jid.2023.07.029. https://pubmed.ncbi.nlm.nih.gov/37863387/

4. Dai, Feibiao, Hu, Chengyun, Li, Xue, Dong, Yongfei, Tang, Chaoliang. 2023. Cav3.2 channel regulates cerebral ischemia/reperfusion injury: a promising target for intervention. In Neural regeneration research, 19, 2480-2487. doi:10.4103/1673-5374.390966. https://pubmed.ncbi.nlm.nih.gov/38526284/

5. Gadotti, Vinicius M, Kreitinger, Joanna M, Wageling, Nicholas B, Diaz, Philippe, Zamponi, Gerald W. 2020. Cav3.2 T-type calcium channels control acute itch in mice. In Molecular brain, 13, 119. doi:10.1186/s13041-020-00663-9. https://pubmed.ncbi.nlm.nih.gov/32873320/

6. Candelas, Miriam, Reynders, Ana, Arango-Lievano, Margarita, Bourinet, Emmanuel, Méry, Pierre-François. 2019. Cav3.2 T-type calcium channels shape electrical firing in mouse Lamina II neurons. In Scientific reports, 9, 3112. doi:10.1038/s41598-019-39703-3. https://pubmed.ncbi.nlm.nih.gov/30816223/