Mechanisms Sensing and Modulating Signals Arising From Cell Swelling

Abstract

Cell volume alterations are involved in numerous cellular events like epithelial transport, metabolic processes, hormone secretion, cell migration, proliferation and apoptosis. Above all it is a need for every cell to counteract osmotic cell swelling in order to avoid cell damage. The defence against excess cell swelling is accomplished by a reduction of the intracellular osmolarity by release of organic- or inorganic osmolytes from the cell or by synthesis of osmotically less active macromolecules from their specific subunits. De-spite the large amount of experimental data that has accumulated, the intracellular mechanisms underlying the sensing of cell volume perturbations and the activation of volume compensatory processes, commonly summarized as regulatory volume decrease (RVD), are still only partly revealed. Moving into this field opens a complex scenario of molecular rearrangements and interactions involving intracellular messengers such as calcium, phosphoinositides and inositolphosphates as well as phosphoryla-tion/dephosphorylation processes and cytoskeletal reorganization with marked cell type- and tissue specific variations. Even in one and the same cell type significant differences regarding the activated pathways during RVD may be evident. This makes it virtually im-possible to unambigously define common sensing- and sinaling pathways used by differ-ent cells to readjust their celll volume, even if all these pathways converge to the activa-tion of comparatively few sets of effectors serving for osmolyte extrusion, including ion channels and transporters. This review is aimed at providing an insight into the manifold cellular mechanisms and alterations occuring during cell swelling and RVD.

Regulation of volume-regulated outwardly rectifying anion channels by phosphatidylinositol 3,4,5-trisphosphate in mouse ventricular cells

“…We conclude that PIP3 is more directly linked to the activation of VRAC current their effects on PIP3-regulated transporters and channels (4,8), further studies are necessary to clarify to what extent PI3K activation can increase the PIP3 level in intact cardiac cells. As with the relationship between cell swelling and PI3K-related signaling pathways, several reports have shown that mechanical stretch of membrane and cell swelling cause activation of PI3K (16), and the activated PI3K has been suggested to trigger some downstream signaling cascades leading to the activation of VRAC current (5,7,26,33). For example, Baumgarten and his colleagues (5) showed that ROS production by NADPH oxidase (NOX), which is formed by PI3K-dependent NOX subunits (p47 phox , p67 phox , Rac), was essential for activation of VRAC current in rabbit ventricular cells.…”

A Role for AQP5 in Activation of TRPV4 by Hypotonicity

“…The ability of cells to regulate their volume is essential for maintenance of cellular homeostasis under anisotonic environmental conditions (1)(2)(3). Changes in osmolarity of the extracellular medium induce water fluxes that result in swelling or shrinkage of cells, depending on the osmotic gradient.…”

“…Most cells respond to changes in tonicity and cell volume by initiating mechanisms that allow them to recover their original volume in the continued presence of the osmotic stress. Such regulatory volume changes depend on the activation of cation and anion permeabilties that reverse the osmotic gradient and direction of water flow (1)(2)(3)(4). Emerging studies demonstrate that regulatory volume changes are critical for cell survival and also for regulation of cellular processes such as gene transcription and proliferation (1).…”

Cell Swelling Stimulates Cytosol to Membrane Transposition of ICln

“…Interestingly, these channels are also permeable to cations, organic osmolytes, and possibly ATP. Therefore, the (an)ion channels and the respective currents that are activated by cell swelling have recently been termed and are here referred to as regulatory volume decrease channels/currents (RVDC) (3,4).…”

“…It is however still a matter of debate, as to whether the protein itself is a part of the molecular RVDC complex or rather acts as a regulator thereof (4,14), e.g. by interacting with integral membrane proteins or membrane-associated molecules.…”