Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC: part 2: its activation mechanisms and essential roles in organic signal release

Abstract

The volume-sensitive outwardly rectifying or volume-regulated anion channel, VSOR/VRAC, which was discovered in 1988, is expressed in most vertebrate cell types, and is essentially involved in cell volume regulation after swelling and in the induction of cell death. This series of review articles describes what is already known and what remains to be uncovered about the functional and molecular properties as well as the physiological and pathophysiological roles of VSOR/VRAC. This Part 2 review article describes, from the physiological and pathophysiological standpoints, first the pivotal roles of VSOR/VRAC in the release of autocrine/paracrine organic signal molecules, such as glutamate, ATP, glutathione, cGAMP, and itaconate, as well as second the swelling-independent and -dependent activation mechanisms of VSOR/VRAC. Since the pore size of VSOR/VRAC has now well been evaluated by electrophysiological and 3D-structural methods, the signal-releasing activity of VSOR/VRAC is here discussed by comparing the molecular sizes of these organic signals to the channel pore size. Swelling-independent activation mechanisms include a physicochemical one caused by the reduction of intracellular ionic strength and a biochemical one caused by oxidation due to stimulation by receptor agonists or apoptosis inducers. Because some organic substances released via VSOR/VRAC upon cell swelling can trigger or augment VSOR/VRAC activation in an autocrine fashion, swelling-dependent activation mechanisms are to be divided into two phases: the first phase induced by cell swelling per se and the second phase caused by receptor stimulation by released organic signals.

Keywords: ATP; LRRC8; Organic signal; Pore size; ROS; Volume-sensitive anion channel.

Fig. 1

Autocrine/paracrine signaling roles of glutamate and ATP released via VSOR/VRAC and Maxi-Cl upon cell swelling in VSOR/VRAC activation. First ((1): brown arrows), such released glutamate and ATP activate, in an autocrine fashion, VSOR/VRAC via stimulation of GPCRs (mGluR and P2YR) in a cell in response to osmotic swelling. Second ((2): violet arrows), glutamate and ATP then activate, in a paracrine fashion, VSOR/VRAC via stimulation of GPCRs in another neighboring cell even in the absence of swelling. These glutamate and ATP may also trigger (black arrows), in a paracrine fashion, induction of inflammation in the surrounding cells/tissues from which BK and S1P are thereafter released. Third ((3): blue arrows), BK and S1P then activate VSOR/VRAC via stimulation of their receptors (B2R and S1PR1). (See text for details.)

Fig. 2

The activation mechanisms of VSOR/VRAC. A Swelling-independent activation physicochemically induced by the Γ_in reduction. B Swelling-independent activation biochemically induced by oxidation due to NOX-mediated ROS production in response to activation of GPCRs and death receptors. C First-phase swelling-induced ATP-dependent activation in association with swelling-triggered activation of TRPM7 which physically interacts with LRRC8A. Here, the ATP dependence is assumed to be granted by some ATP-bound ABC protein (here called ABCX) which is assumed to physically interact with VSOR/VRAC molecules, presumably at the convex outside of the LRRD of LRRC8A, but released therefrom upon osmotic swelling followed by an interaction with some cytoskeletal component. D Second-phase swelling-induced ROS-dependent activation due not only to NOX-mediated ROS production after GPCR stimulation induced by glutamate (Glu⁻) and ATP⁴⁻ released as a result of first-phase activation of VSOR/VRAC but also to the elevation of cytosolic ROS level as a result of the loss of intracellular GSH caused by VSOR/VRAC-mediated GSH⁻ release. (See text for details.)