TMEM63B, a mechanosensitive and osmosensitive ion channel, plays crucial roles in various biological processes. It converts physical forces into electrical signals or triggers intracellular cascades, allowing cells to respond to osmotic and mechanical stress. It is involved in multiple pathways related to fluid homeostasis, cell volume regulation, and mechanotransduction, and is of great biological importance in maintaining normal physiological functions [1,2,3,4]. Genetic models, such as knockout (KO) mice, are valuable tools for studying its functions.

In KO mouse models, deletion of TMEM63B in subfornical organ (SFO) neurons impaired hyperosmolarity-induced drinking behavior, indicating its role as an osmosensor for thirst drive [2]. In lung, loss of TMEM63A/B (including TMEM63B) led to atelectasis and respiratory failure due to surfactant secretion deficit, suggesting its role in lung inflation-induced surfactant secretion [3]. In the inner ear, genetic deletion of TMEM63B caused necroptosis of outer hair cells and progressive hearing loss, showing it is an osmosensor required for hearing [4]. In intestinal stem cells, deletion of TMEM63B decelerated intestinal motility, impaired digestion, and attenuated cell proliferation [5].

In conclusion, through model-based research, TMEM63B has been shown to be essential in processes like thirst perception, lung function, hearing, and intestinal function. Studies using KO mouse models have significantly contributed to understanding its role in these physiological processes and associated disease conditions such as developmental and epileptic encephalopathies, where heterozygous variants of TMEM63B are associated with severe neurological phenotypes [1].

References:

1. Vetro, Annalisa, Pelorosso, Cristiana, Balestrini, Simona, Ratto, Gian Michele, Guerrini, Renzo. 2023. Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration. In American journal of human genetics, 110, 1356-1376. doi:10.1016/j.ajhg.2023.06.008. https://pubmed.ncbi.nlm.nih.gov/37421948/

2. Yang, Guolin, Jia, Min, Li, Guizhou, Yang, Jian-Jun, Shi, Yun Stone. 2024. TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons. In Cell discovery, 10, 1. doi:10.1038/s41421-023-00628-x. https://pubmed.ncbi.nlm.nih.gov/38172113/

3. Chen, Gui-Lan, Li, Jing-Yi, Chen, Xin, Zhang, Jin, Zeng, Bo. 2024. Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation-induced surfactant secretion. In The Journal of clinical investigation, 134, . doi:10.1172/JCI174508. https://pubmed.ncbi.nlm.nih.gov/38127458/

4. Du, Han, Ye, Chang, Wu, Dan, Wan, Guoqiang, Shi, Yun Stone. . The Cation Channel TMEM63B Is an Osmosensor Required for Hearing. In Cell reports, 31, 107596. doi:10.1016/j.celrep.2020.107596. https://pubmed.ncbi.nlm.nih.gov/32375046/

5. Tu, Jing-Jing, Zang, Yan-Yu, Shi, Yun Stone, Teng, Xiao-Yu. 2024. The TMEM63B Channel Facilitates Intestinal Motility and Enhances Proliferation of Intestinal Stem Cells. In Cells, 13, . doi:10.3390/cells13211784. https://pubmed.ncbi.nlm.nih.gov/39513891/