Car3, also known as carbonic anhydrase III, is an enzyme that catalyzes the reversible condensation of water and carbon dioxide to carbonic acid, which then dissociates to bicarbonate [2]. It is nutritionally regulated at both the mRNA and protein level and is highly enriched in tissues involved in fat synthesis and storage, such as the liver, adipose tissues, and skeletal muscle. In addition to its role in CO₂ hydration, it is involved in multiple biological processes [1]. Gene knockout models have been crucial in studying its function.

In cardiac repair post myocardial infarction (MI), CAR3 deficiency in mice leads to weakened collagen density, enlarged infarct size, and aggravated cardiac dysfunction. CAR3 is up-regulated in cardiac fibroblasts in the infarct area during the reparative phase of MI. Mechanistically, CAR3 stabilizes Smad7 protein via modulating its acetylation, dampening phosphorylation of Smad2 and Smad3, thus promoting fibroblast activation and cardiac wound repair through the Smad7-TGF-β/Smad2/3 signaling pathway [1]. In the context of myasthenia gravis, inhibition of CAR3 in an experimental autoimmune myasthenia gravis animal model and C2C12 skeletal muscle cells promotes CHRN internalization via a lipid raft-mediated pathway, leading to accelerated degradation of postsynaptic CHRN. Activation of CAR3 reduces CHRN degradation by suppressing receptor endocytosis [3].

In conclusion, Car3 plays essential roles in biological processes, especially in cardiac repair post-MI and maintaining CHRN homeostasis in the neuromuscular junction. Gene knockout mouse models have been instrumental in revealing its functions in these disease-related contexts, providing insights into potential therapeutic strategies for myocardial infarction and myasthenia gravis.

References:

1. Su, Yuanyuan, Shi, Dongmei, Xia, Guofang, Shen, Chengxing, Xu, Congfeng. 2024. Carbonic Anhydrase 3 is required for cardiac repair post myocardial infarction via Smad7-Smad2/3 signaling pathway. In International journal of biological sciences, 20, 1796-1814. doi:10.7150/ijbs.91396. https://pubmed.ncbi.nlm.nih.gov/38481818/

2. Renner, Sarah W, Walker, Lauren M, Forsberg, Lawrence J, Sexton, Jonathan Z, Brenman, Jay E. 2017. Carbonic anhydrase III (Car3) is not required for fatty acid synthesis and does not protect against high-fat diet induced obesity in mice. In PloS one, 12, e0176502. doi:10.1371/journal.pone.0176502. https://pubmed.ncbi.nlm.nih.gov/28437447/

3. Du, Ailian, Huang, Shiqian, Zhao, Xiaonan, Chen, Xiangjun, Xu, Congfeng. 2017. Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis. In Autophagy, 13, 1981-1994. doi:10.1080/15548627.2017.1375633. https://pubmed.ncbi.nlm.nih.gov/28933591/