Transient receptor potential melastatin 4 and cell death

Abstract

Cell death proceeds by way of a variety of “cell death subroutines,” including several types of “apoptosis,” “regulated necrosis,” and others. “Accidental necrosis” due to profound adenosine triphosphate (ATP) depletion or oxidative stress is distinguished from regulated necrosis by the absence of death receptor signaling. However, both accidental and regulated necrosis have in common the process of “oncosis,” a physiological process characterized by Na+ influx and cell volume increase that, in necrotic cell death, is required to produce the characteristic features of membrane blebbing and membrane rupture. Here, we review emerging evidence that the monovalent cation channel, transient receptor potential melastatin 4 (TRPM4), is involved in the cell death process of oncosis. Potential involvement of TRPM4 in oncosis is suggested by the fact that the two principal regulators of TRPM4, intracellular ATP and Ca2+, are both altered during necrosis in the direction that causes TRPM4 channel opening. Under physiological conditions, activation of TRPM4 promotes Na+ influx and cell depolarization. Under pathological conditions, unchecked activation of TRPM4 leads to Na+ overload, cell volume increase, blebbing and cell membrane rupture, the latter constituting the irreversible end stage of necrosis. Emerging data indicate that TRPM4 plays a crucial role as end executioner in the accidental necrotic death of ATP-depleted or redox-challenged endothelial and epithelial cells, both in vitro and in vivo. Future studies will be needed to determine whether TRPM4 also plays a role in regulated necrosis and apoptosis.

9-Phenanthrol, a TRPM4 Inhibitor, Protects Isolated Rat Hearts from Ischemia–Reperfusion Injury

“…TRPM4 has been linked to diverse physiological functions such as protection against Ca 2+ overload, regulating the levels of intracellular ATP and reactive oxygen species, and cell death [25], [26], [27], [28]. Recently, Schattling et al reported that TRPM4 in neurons contributes toward inflammation-induced neurodegeneration by mediating cell death [29], which corresponds to the cardioprotective effect of 9-phenanthrol detected here.…”

Sulfonylurea Receptor 1 Expression in Human Cerebral Infarcts

“…This process is distinct from regulated necrosis and results not only in cytoplasmic volume increase but also membrane blebbing and eventual membrane rupture. Trpm4, a monovalent cation channel, is activated in pathologic states and has been shown to play a critical role in this process of oncosis, likely functioning as an end-executioner in accidental necrotic cell death (16). This channel has recently been shown to coassociate with Sur1, which regulates its activity (14).…”

Glibenclamide for the Treatment of Acute CNS Injury

“…Recent publications have reviewed the roles of Sur1 [34], Trpm4 [35] and K ATP [36,37,38] channels in CNS injury. However, our purpose here is to take a different perspective and highlight the potential uses for glibenclamide in treating the injured brain.…”