Trpm4 is a Ca(2+)-activated nonselective cation channel [2]. It allows Na(+) entry into the cell upon activation but is impermeable to Ca(2+). It is widely expressed in the body and plays a role in regulating intracellular Ca(2+) homeostasis/dynamics, which is associated with various cellular functions [2,5].

In the heart, gain-of-function mutations of Trpm4 are a cause of familial cardiac block. Trpm4 -/- mice display a reduced burden of Ca2+-dependent cardiac arrhythmias, indicating that Trpm4 contributes to the development of such arrhythmias by regulating cell excitability during Ca2+ overload [4,5]. In cancer, Trpm4 expression has been linked to behaviors like cancer cell migration and invasion in prostate cancer and large B cell lymphoma. Cancer cells selected for resistance to necrosis-inducing agents BHPI and ErSO exhibit TRPM4 downregulation, and Trpm4 knockout abolishes ErSO-induced regression of breast tumors in mice, suggesting Trpm4 plays a role in necrosis-based cancer immunotherapies [1,3].

In conclusion, Trpm4 is crucial for regulating intracellular Ca(2+)-related functions. Gene knockout mouse models have revealed its significance in cardiac electrophysiology, specifically in the development of arrhythmias, and in cancer, particularly in relation to necrosis-based immunotherapies. Understanding Trpm4 through these models provides insights into disease mechanisms and potential therapeutic targets.