TRPM4, a Ca(2+)-activated nonselective cation channel, is widely expressed in the body [2]. It allows Na(+) entry upon activation but is impermeable to Ca(2+), and is regulated by factors like temperature and Pi(4,5)P2. By influencing membrane potential through sodium entry, it impacts calcium influx regulation, thus playing a role in calcium homeostasis which is crucial for many cellular functions [1].

TRPM4 knockout (TKO) mouse models have revealed its significance in various processes. In cancer, TKO abolished ErSO-induced regression of breast tumors and reversed cell death induced by multiple necrosis-inducing cancer therapies, suggesting TRPM4 is pivotal in sustaining lethal anticipatory unfolded protein response (a-UPR) hyperactivation that mediates anticancer activity [3]. In the heart, mutations in the TRPM4 gene are associated with cardiac conduction disorders, and in mice, pharmacological inhibition of TRPM4 prevents cardiac ischaemia-reperfusion injuries and reduces arrhythmias [2,5].

In conclusion, TRPM4 is essential for regulating cellular functions related to calcium homeostasis. Its role in diseases such as cancer and cardiac arrhythmias has been illuminated through the use of knockout mouse models. These models have provided valuable insights into its functions, offering potential for developing new therapeutic strategies for these diseases [1,3,4,5].

References:

1. Gao, Yahui, Liao, Ping. 2019. TRPM4 channel and cancer. In Cancer letters, 454, 66-69. doi:10.1016/j.canlet.2019.04.012. https://pubmed.ncbi.nlm.nih.gov/30980865/

2. Mathar, Ilka, Jacobs, Griet, Kecskes, Miklos, Philippaert, Koenraad, Vennekens, Rudi. . TRPM4. In Handbook of experimental pharmacology, 222, 461-87. doi:10.1007/978-3-642-54215-2_18. https://pubmed.ncbi.nlm.nih.gov/24756717/

3. Ghosh, Santanu, Yang, Rachel, Duraki, Darjan, Hergenrother, Paul J, Shapiro, David J. . Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy-Induced Necrosis. In Cancer research, 83, 3115-3130. doi:10.1158/0008-5472.CAN-23-0157. https://pubmed.ncbi.nlm.nih.gov/37522838/

4. Hu, Yaopeng, Cang, Jiehui, Hiraishi, Keizo, Fujita, Takayuki, Inoue, Ryuji. 2023. The Role of TRPM4 in Cardiac Electrophysiology and Arrhythmogenesis. In International journal of molecular sciences, 24, . doi:10.3390/ijms241411798. https://pubmed.ncbi.nlm.nih.gov/37511555/

5. Guinamard, Romain, Bouvagnet, Patrice, Hof, Thomas, Simard, Christophe, Sallé, Laurent. 2015. TRPM4 in cardiac electrical activity. In Cardiovascular research, 108, 21-30. doi:10.1093/cvr/cvv213. https://pubmed.ncbi.nlm.nih.gov/26272755/