More than just a pressure relief valve: physiological roles of volume-regulated LRRC8 anion channels

Abstract

The volume-regulated anion channel (VRAC) is a key player in the volume regulation of vertebrate cells. This ubiquitously expressed channel opens upon osmotic cell swelling and potentially other cues and releases chloride and organic osmolytes, which contributes to regulatory volume decrease (RVD). A plethora of studies have proposed a wide range of physiological roles for VRAC beyond volume regulation including cell proliferation, differentiation and migration, apoptosis, intercellular communication by direct release of signaling molecules and by supporting the exocytosis of insulin. VRAC was additionally implicated in pathological states such as cancer therapy resistance and excitotoxicity under ischemic conditions. Following extensive investigations, 5 years ago leucine-rich repeat-containing family 8 (LRRC8) heteromers containing LRRC8A were identified as the pore-forming components of VRAC. Since then, molecular biological approaches have allowed further insight into the biophysical properties and structure of VRAC. Heterologous expression, siRNA-mediated downregulation and genome editing in cells, as well as the use of animal models have enabled the assessment of the proposed physiological roles, together with the identification of new functions including spermatogenesis and the uptake of antibiotics and platinum-based cancer drugs. This review discusses the recent molecular biological insights into the physiology of VRAC in relation to its previously proposed roles.

The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

“…In contrast, a ~40% increase in p-IRF3 signaling was observed in LRRC8D knockout clones. Negligible differences were observed in LRRC8B and LRRC8E knockouts (average decreases of 5% and 8%, respectively), consistent with LRRC8B not playing a role in transport of large anions (Lutter et al, 2017;Schober et al, 2017) and LRRC8E expression being restricted (Chen et al, 2019). Together, these data validate the effects observed in the whole-genome screen that LRRC8 paralogs play differential regulatory roles in extracellular cGAMP signaling.…”

“…It is becoming clear that VRAC's namesake function in regulation of cell volume represents only a subset of the broad physiological roles the channels play. LRRC8A has been linked to cellular development, migration, and apoptosis, as well as cell-to-cell communication by regulating insulin release and mediating excitatory astrocyte-neuron signaling (Chen et al, 2019;Osei-Owusu et al, 2018). We identify immunostimulatory 2'3'-cyclic dinucleotides as a new class of substrates transported by LRRC8A-containing channels.…”

“…LRRC8A was recently identified as an essential component of the volume-regulated anion channel (VRAC) that resides on the plasma membrane (Qiu et al, 2014;Voss et al, 2014). Upon cell swelling or sensing of various stimuli, opening of VRAC leads to outward flow of chloride ions, organic osmolytes, and water to facilitate regulated volume decrease (Chen et al, 2019;Osei-Owusu et al, 2018;Strange et al, 2019). In ?…”

“…Interestingly, the transmembrane pore of LRRC8A channels shares structural similarities with that of connexins-known gap junction cGAMP transporters-however LRRC8A channels open to the extracellular space instead of linking together the cytosol between two cells (Deneka et al, 2018). LRRC8A was recently identified as an essential component of the long sought-after volume-regulated anion channel (VRAC) (Qiu et al, 2014;Voss et al, 2014), but its role appears to extend beyond regulation of cell-intrinsic physiology as LRRC8A-containing channels are now being discovered to mediate cell-cell communication via transport of signaling molecules (Chen et al, 2019).…”

The LRRC8 volume‐regulated anion channel inhibitor, DCPIB, inhibits mitochondrial respiration independently of the channel

“…Volume‐Regulated Anion Channels (VRAC) are ubiquitously expressed in mammalian cells where they play key roles in cell volume regulation and other fundamentally important cellular processes (Chen et al, ; Jentsch, ; Mongin, ; Osei‐Owusu, Yang, Vitery, & Qiu, ; Pedersen, Klausen, & Nilius, ; Stauber, ; Strange, Yamada, & Denton, ). Opening of VRACs by osmotic cell swelling allows chloride and small organic osmolytes (e.g., taurine, glutamate) to leave the cell, followed by osmotic water, to help restore cell volume and prevent membrane rupture.…”