Cell Death Induction and Protection by Activation of Ubiquitously Expressed Anion/Cation Channels. Part 1: Roles of VSOR/VRAC in Cell Volume Regulation, Release of Double-Edged Signals and Apoptotic/Necrotic Cell Death.

Cell volume regulation (CVR) is essential for survival and functions of animal cells. Actually, normotonic cell shrinkage and swelling are coupled to apoptotic and necrotic cell death and thus called the apoptotic volume decrease (AVD) and the necrotic volume increase (NVI), respectively. A number of ubiquitously expressed anion and cation channels are involved not only in CVD but also in cell death induction. This series of review articles address the question how cell death is induced or protected with using ubiquitously expressed ion channels such as swelling-activated anion channels, acid-activated anion channels and several types of TRP cation channels including TRPM2 and TRPM7. The Part 1 focuses on the roles of the volume-sensitive outwardly rectifying anion channels (VSOR), also called the volume-regulated anion channel (VRAC), which is activated by cell swelling or reactive oxygen species (ROS) in a manner dependent on intracellular ATP. First we describe phenotypical properties, the molecular identity, and physical pore dimensions of VSOR/VRAC. Second, we highlight the roles of VSOR/VRAC in the release of organic signaling molecules, such as glutamate, glutathione, ATP and cGAMP, that play roles as double-edged swords in cell survival. Third, we discuss how VSOR/VRAC is involved in CVR and cell volume dysregulation as well as in the induction of or protection from apoptosis, necrosis and regulated necrosis under pathophysiological conditions.