The identification of a volume‐regulated anion channel: an amazing Odyssey

Abstract

The volume-regulated anion channel (VRAC) plays a pivotal role in cell volume regulation in essentially all cell types studied. Additionally, VRAC appears to contribute importantly to a wide range of other cellular functions and pathological events, including cell motility, cell proliferation, apoptosis and excitotoxic glutamate release in stroke. Although biophysically, pharmacologically and functionally thoroughly described, VRAC has until very recently remained a genetic orphan. The search for the molecular identity of VRAC has been long and has yielded multiple potential candidates, all of which eventually turned out to have properties not fully compatible with those of VRAC. Recently, two groups have independently identified the protein leucine-rich repeats containing 8A (LRRC8A), belonging to family of proteins (LRRC8A-E) distantly related to pannexins, as the likely pore-forming subunit of VRAC. In this brief review, we summarize the history of the discovery of VRAC, outline its basic biophysical and pharmacological properties, link these to several cellular functions in which VRAC appears to play important roles, and sketch the amazing search for the molecular identity of this channel. Finally, we describe properties of the LRRC8 proteins, highlight some features of the LRRC8A knockout mouse and discuss the impact of the discovery of LRRC8 as VRAC on future research.

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…120 currents. 52,53 Native CaCC in rabbit pulmonary artery myocytes exhibit 2 conductance states with 1.8 and 3.5 pS when examined in a single-channel patch-clamp experiment. 54 ANO1 unitary conductance is measured at 8.3 pS from the slope conductance 5 and at 3.5 pS from noise analysis.…”

Channels and Volume Changes in the Life and Death of the Cell

“…It also points to the possibility that one or some of the LCRR8 subunits forming VRAC contain the sensor for changes in ionic strength, the proposed channel gating (Cannon et al, 1998;Nilius et al, 1998;Sabirov et al, 2000). The relevance of these findings to define the molecular identity of VRAC is extensively discussed in several excellent recent reviews (Pedersen et al, 2015(Pedersen et al, , 2016Stauber, 2015;Jentsch et al, 2016).…”

Cl− channels in apoptosis

“…Anion channels are also required for apoptotic cell death, to lower cytosolic anion concentration along with the drastic decrease of intracellular K + concentration (Okada et al 2006). The proteins ClC-3, VDAC, and CLCA were discussed in the past as apoptotic anion channels, at a time when the volume-regulated anion channel (VRAC, VSOR, VSOA) remained enigmatic (Gulbins et al 2000;Okada et al 2006;Pedersen et al 2015). The aim of the present study is to review current knowledge on anion channels involved in apoptotic cell shrinkage and provide additional novel data that support a role of Abstract A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K + , Cl − , and organic osmolytes to drive osmotic water movement and cell shrinkage.…”