Receptor‐mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD)

Abstract

A fundamental property of animal cells is the ability to regulate their own cell volume. Even under hypotonic stress imposed by either decreased extracellular or increased intracellular osmolarity, the cells can re‐adjust their volume after transient osmotic swelling by a mechanism known as regulatory volume decrease (RVD). In most cell types, RVD is accomplished mainly by KCl efflux induced by parallel activation of K+ and Cl− channels. We have studied the molecular mechanism of RVD in a human epithelial cell line (Intestine 407). Osmotic swelling results in a significant increase in the cytosolic Ca2+ concentration and thereby activates intermediate‐conductance Ca2+‐dependent K+ (IK) channels. Osmotic swelling also induces ATP release from the cells to the extracellular compartment. Released ATP stimulates purinergic ATP (P2Y2) receptors, thereby inducing phospholipase C‐mediated Ca2+ mobilization. Thus, RVD is facilitated by stimulation of P2Y2 receptors due to augmentation of IK channels. In contrast, stimulation of another G protein‐coupled Ca2+‐sensing receptor (CaR) enhances the activity of volume‐sensitive outwardly rectifying Cl− channels, thereby facilitating RVD. Therefore, it is possible that Ca2+ efflux stimulated by swelling‐induced and P2Y2 receptor‐mediated intracellular Ca2+ mobilization activates the CaR, thereby secondarily upregulating the volume‐regulatory Cl− conductance. On the other hand, the initial process towards apoptotic cell death is coupled to normotonic cell shrinkage, called apoptotic volume decrease (AVD). Stimulation of death receptors, such as TNFα receptor and Fas, induces AVD and thereafter biochemical apoptotic events in human lymphoid (U937), human epithelial (HeLa), mouse neuroblastoma × rat glioma hybrid (NG108‐15) and rat phaeochromocytoma (PC12) cells. In those cells exhibiting AVD, facilitation of RVD is always observed. Both AVD induction and RVD facilitation as well as succeeding apoptotic events can be abolished by prior treatment with a blocker of volume‐regulatory K+ or Cl− channels, suggesting that AVD is caused by normotonic activation of ion channels that are normally involved in RVD under hypotonic conditions. Therefore, it is likely that G protein‐coupled receptors involved in RVD regulation and death receptors triggering AVD may share common downstream signals which should give us key clues to the detailed mechanisms of volume regulation and survival of animal cells. In this Topical Review, we look at the physiological ionic mechanisms of cell volume regulation and cell death‐associated volume changes from the facet of receptor‐mediated cellular processes.

Organellar mechanosensitive channels in fission yeast regulate the hypo-osmotic shock response

“…msy1 -msy2 -undergoes osmotic stress-induced cell death. Upon hypo-osmotic shock, mammalian cells undergo osmotic stress-induced death, such as necrosis 28 , whereas prokaryotic cells experience cell lysis 6 . Thus, to examine whether the decreased viability of msy2 -cells and msy1 -msy2 -cells is due to osmoticinduced cell death or cell lysis, we performed a time-lapse imaging analysis with cells that express EGFP to monitor cell lysis.…”

“…0 16 20 21 23 25 32 45 58 71 129 0 16 20 21 23 25 32 45 58 71 129 30 40 50 60 70 80 90 Cell volume regulation has been well studied in mammalian cells. Following hypo-osmotic shock, the cells swell quickly, but soon start recovering their volume near the original level by a mechanism called regulatory volume decrease (RVD) 28 . During this process, cell swelling induces a [Ca 2 + ] i increase that has a regulatory role for ion homoeostasis across the plasma membrane.…”

Methods for evaluation of platelet function

“…This can be measured with a spectrophotometer. There are conflicting results on the correlation with platelet viability [3,4], [5].…”

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…In majority of cell types, cell swelling activates Cl − efflux via the above mentioned VRAC in conjunction with K + loss via SWELLING-ACTIVATED K + CHANNELS. Under physiological conditions these two independent permeability pathways mediate electrically coupled loss of K + and Cl − , which is accompanied by an efflux of osmotically obligated water, and REGULATORY VOLUME DECREASE, or RVD [30,33,34]. However, in pathology, anoxic and/or glutamate-driven depolarization disrupts cell volume regulation due to an inhibition of the Na + ,K + -pump, dissipation of K + and Cl − electrochemical gradients, and blockade of volume regulatory channels [13,21,25,35].…”

“…Uncontrolled cell swelling is frequently associated with necrosis and may be harmful to neuronal and glial cells for multiple reasons [13,30]. The simplest mechanism of cell damage is osmotic lysis.…”