LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions

Serra, Selma A.; Stojakovic, Predrag; Amat, Ramon; Rubio-Moscardó, Fanny; Latorre, Pablo; Seisenbacher, Gerhard; Canadell, David; Böttcher, René; Aregger, Michael; Moffat, Jason; Nadal, Eulàlia de; Valverde, Miguel A.; Posas, Francesc

doi:10.1073/pnas.2025013118

Cited by 33 publications

(18 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with refs. 40 and 41 , recovery was still incomplete 2 h after the shock. Membrane tension had very different recovery dynamics: It started recovering only 50 min after the shock, but the recovery is fast and complete after 80 min ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 95%

Passive coupling of membrane tension and cell volume during active response of cells to osmosis

Roffay

Molinard

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

During osmotic changes of their environment, cells actively regulate their volume and plasma membrane tension that can passively change through osmosis. How tension and volume are coupled during osmotic adaptation remains unknown, as their quantitative characterization is lacking. Here, we performed dynamic membrane tension and cell volume measurements during osmotic shocks. During the first few seconds following the shock, cell volume varied to equilibrate osmotic pressures inside and outside the cell, and membrane tension dynamically followed these changes. A theoretical model based on the passive, reversible unfolding of the membrane as it detaches from the actin cortex during volume increase quantitatively describes our data. After the initial response, tension and volume recovered from hypoosmotic shocks but not from hyperosmotic shocks. Using a fluorescent membrane tension probe (fluorescent lipid tension reporter [Flipper-TR]), we investigated the coupling between tension and volume during these asymmetric recoveries. Caveolae depletion and pharmacological inhibition of ion transporters and channels, mTORCs, and the cytoskeleton all affected tension and volume responses. Treatments targeting mTORC2 and specific downstream effectors caused identical changes to both tension and volume responses, their coupling remaining the same. This supports that the coupling of tension and volume responses to osmotic shocks is primarily regulated by mTORC2.

show abstract

Section: Resultsmentioning

confidence: 95%

Passive coupling of membrane tension and cell volume during active response of cells to osmosis

Roffay

Molinard

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

show abstract

“…The observed increase of r EGFP due to increased cytoplasmic MMC is caused primarily by the decrement of its fluorescence lifetime, τ EGFP ( Fig 2D , S2C )(Suhling et al ., 2002). While 950mOsm hypertonic shock with dextrose causes about a 20% increase in r BGFP , without recovery ( Fig 2B ), 950mOsm shock with NaCl causes a smaller change (~10%) in r EGFP ( Fig S2D ), because the rapid exchange of Cl - and Na + ions can alleviate the adverse effects of excessive osmotic imbalance (Vallés et al ., 2015; Serra et al ., 2021). Reversing the osmotic imbalance (950mOsm) with isotonic DMEM causes immediate reversal of r EGFP to pre-shock value ( Fig 2E ).…”

Section: Resultsmentioning

confidence: 99%

“…Cell volume regulatory apparatus can be broken down into three parts (i) cell volume sensor (ii) intracellular signaling cascades, which receives information related to change in volume and (iii) the volume regulatory action, leading to resetting of cell volume to a set-point. Regulatory volume change during osmotic imbalance involves the exchange of organic and inorganic osmolytes (Jentsch, 2016; Serra et al ., 2021), which are smaller in size than the macromolecular crowders. Thus, there can be two possibly distinct features that could act as a volume sensor.…”

Section: Resultsmentioning

confidence: 99%

Probing the role of macromolecular crowding in cell volume regulation using fluorescence anisotropy

Biswas

Ray

Jana

et al. 2022

Preprint

View full text Add to dashboard Cite

Cytoplasmic macromolecular crowding (MMC) influences multiple cellular functions. Using fluorescence anisotropy of EGFP, we explore the homeostasis of MMC in the cytoplasm and its role in cell volume regulation. Individual cells of different lineages maintain a distinctly unique average cytoplasmic MMC for considerably long durations. Despite diffusion, actin cytoskeleton facilitates spatially heterogeneous MMC in the cytoplasm. While hypertonic-stress triggers regulatory volume increase (RVI), other methods of increasing cytoplasmic MMC fail to start RVI, suggesting that cells lack capabilities for MMC homeostasis. During spreading or microtubule-depolymerized state, cells neglect changes in cytoplasmic MMC to undergo volume regulation. Inhibition of TNFR1 increases the membrane tension and deprives cells of their ability to undergo volume regulation. Current understanding contemplates that cytoplasmic MMC, the mechanical state of the plasma membrane or the actin cytoskeleton, could be sensors for cell volume regulation. Our observations establish the irrelevance of cytoplasmic MMC and the significance of plasma membrane tension in setting off the cell volume regulation machinery.

show abstract

“…Additionally, the treatment with GABA has prevented the secretion of IL-2 and IFN-γ on CD8 + T cells (Feske et al, 2012). Finally, the LRRC8-A channel has been identified on T cells and shown to be important for T cell development, function and survival (Kumar et al, 2014;Serra et al, 2021).…”

Section: Anionic Channelsmentioning

confidence: 99%

Modulation of Adaptive Immunity and Viral Infections by Ion Channels

et al. 2021

View full text Add to dashboard Cite

Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca2+) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+ in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+ concentrations and the mobilization of this cation through Ca2+ channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+ through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+ channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+ channels in the context of viral infections and their contribution to the modulation of adaptive immune responses.

show abstract

LRRC8A-containing chloride channel is crucial for cell volume recovery and survival under hypertonic conditions

Cited by 33 publications

References 63 publications

Passive coupling of membrane tension and cell volume during active response of cells to osmosis

Passive coupling of membrane tension and cell volume during active response of cells to osmosis

Probing the role of macromolecular crowding in cell volume regulation using fluorescence anisotropy

Modulation of Adaptive Immunity and Viral Infections by Ion Channels

Contact Info

Product

Resources

About