Sensors, Transducers, and Effectors That Regulate Cell Size and Shape

Cell volume and shape are stringently regulated. This homeostasis requires the cells to sense their size and shape and to convey this information to effectors that will counteract deformations induced by osmotic or mechanical challenges. The sensors, transducers, and effectors of volume change are the subject of this review. Cell volume and shape are stringently regulated. This homeostasis requires the cells to sense their size and shape and to convey this information to effectors that will counteract deformations induced by osmotic or mechanical challenges. The sensors, transducers, and effectors of volume change are the subject of this review. With few exceptions, the permeability of biological membranes to water is much greater than that to ions and other solutes. As a result, imposition of aniso-osmolar conditions across the plasma membrane causes the rapid net flow of water, and consequently, cell volume changes. When cells face osmotic challenges, they deploy regulatory mechanisms to defend their size and integrity. Moreover, even when bathed in physiological medium, cells experience isotonic volume changes when undergoing sudden gains or losses of solutes due to transport or metabolic stimulation. In addition, the shape of many cells is often altered by externally applied physical forces, by intrinsic cytoskeletal rearrangement, or by remodeling of the substratum. The generation of osmosensitive or mechanosensitive responses can be conceptually divided into three events: sensing the shape or volume change, transmission of the information to the effectors, and execution of the regulatory response. These are discussed in turn below. In principle, three types of parameters could be sensed by cells when their volume is challenged osmotically: the concentration of solutes, the thickness or lateral tension of the bilayer, or cell shape-dependent interactions between macromolecular structures. When cells are swollen or shrunken, the osmolarity and ionic strength of the intra- and extracellular milieu are altered. The abstraction or addition of water changes the concentration of critical substrates and macromolecular crowding in general, and the changes in ionic strength alter the degree of shielding of exposed charges. Although these events have been proposed to mediate volume sensing (1Burg M.B. Cell Physiol. Biochem. 2000; 10: 251-256Crossref PubMed Scopus (82) Google Scholar), we feel that under most conditions, the changes in ionic strength and macromolecular crowding are comparatively small and contribute little to eliciting cellular responses. For example, activation of ion exchangers and cotransporters has been reported when cell volume is altered by <5% (2Parker J.C. Dunham P.B. Minton A.P. J. Gen. Physiol. 1995; 105: 677-699Crossref PubMed Scopus (35) Google Scholar, 3Russell J.M. Physiol. Rev. 2000; 80: 211-276Crossref PubMed Scopus (737) Google Scholar). The accompanying change in macromolecular concentration is minute and unlikely to serve as an effective transducer of information. Pronounced cell swelling will eventually stretch the membrane bilayer in the lateral plane. A variety of channels and transporters respond to such mechanical deformation of the bilayer, affording the cell a simple and direct means of controlling transport for the purpose of volume regulation. However, cells are not smooth spheres, and a vast amount of membrane is folded into filopodia, ruffles, and other protrusions. These can accommodate considerable increases in cell volume without incurring lateral stretching. Therefore, lateral tension of the bilayer signals the activation of volume regulatory effectors mostly in cases of extreme swelling. Instead, we favor the notion that mechanically induced alterations in the interactions between (macro)molecular complexes are mainly responsible for the responses to volume perturbations. Two main types of mechanically induced changes can be envisaged: those resulting from altered curvature of the membrane and those caused by dislodging membrane components from their native interaction with the cytoskeleton or the extracellular matrix. Alterations in membrane curvature can change the physical properties of lipids and potentially alter their metabolism. Inward depression of the membrane (concavity) forces greater spacing between lipid headgroups of the inner monolayer, increasing the exposure of the hydrophobic side chains. The opposite response is experienced by the outer monolayer. Conversely, outward (convex) deformation packs the headgroups of the inner monolayer and vice versa. Greater exposure of the hydrophobic tails makes them more accessible to enzymatic attack (4Lambert I.H. Pedersen S.F. Poulsen K.A. Acta Physiol. (Oxf.). 2006; 187: 75-85Crossref PubMed Scopus (78) Google Scholar, 5Lehtonen J.Y. Kinnunen P.K. Biophys. J. 1995; 68: 1888-1894Abstract Full Text PDF PubMed Scopus (139) Google Scholar). In addition, because some plasmalemmal lipids are anionic, altered packing of headgroups changes the density of interfacial charges. Cell swelling and shrinking can also alter the properties of membrane proteins or lipids independently of membrane curvature. The net displacement of the membrane as the cells swell or shrink can potentially disrupt pre-existing associations between membrane components and less mobile structures, such as the cytoskeleton, the extracellular matrix, or neighboring cells. This results in dissociation of pre-existing complexes and possibly the formation of new ones. In addition, by losing their anchorage, intrinsic membrane proteins can redistribute laterally, which can promote clustering, as reported for integrins (6Schliess F. Haussinger D. Methods Enzymol. 2007; 428: 129-144Crossref PubMed Scopus (13) Google Scholar). Although there are attractive theoretical options to explain how changes in cell shape and volume could be sensed, definitive mechanisms have been identified only in a handful of cases. These include the shrinkage-induced, ligand-independent activation of receptors like the epidermal growth factor receptor (7Sheikh-Hamad D. Gustin M.C. Am. J. Physiol. 2004; 287: F1102-F1110Crossref PubMed Scopus (139) Google Scholar), the osmotically or mechanically provoked activation of TRP 2The abbreviations used are: TRP, transient receptor potential; PIP2, phosphatidylinositol 4,5-bisphosphate; RVI, regulatory volume increase; RVD, regulatory volume decrease; NHE, Na+/H+ exchanger; NKCC, Na+-K+-2Cl– cotransporter; KCC, K+-Cl– cotransporter; HICC, hypertonicity-induced cation channel; VRAC, volume-regulated anion channel. ion channels (8Liedtke C.M. Cole T.S. Biochim. Biophys. Acta. 2002; 1589: 77-88Crossref PubMed Scopus (54) Google Scholar, 9Pedersen S.F. Nilius B. Methods Enzymol. 2007; 428: 183-207Crossref PubMed Scopus (110) Google Scholar), and the volume-induced activation of integrins (6Schliess F. Haussinger D. Methods Enzymol. 2007; 428: 129-144Crossref PubMed Scopus (13) Google Scholar). Changes in cell size trigger a plethora of signaling pathways (Table 1). In fact, a major challenge in the field is to link specific signals with the upstream sensors on one hand and the corresponding downstream effectors on the other.TABLE 1Signaling pathways activated by volume changes and their proposed functions Open table in a new tab Lipids and Lipid-modifying Enzymes-Cell shrinkage increases (10Nasuhoglu C. Feng S. Mao Y. Shammat I. Yamamato M. Earnest S. Lemmon M. Hilgemann D.W. Am. J. Physiol. 2002; 283: C223-C234Crossref PubMed Scopus (76) Google Scholar, 11Yamamoto M. Chen M.Z. Wang Y.J. Sun H.Q. Wei Y. Martinez M. Yin H.L. J. Biol. Chem. 2006; 281: 32630-32638Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 12Nielsen D.K. Jensen A.K. Harbak H. Christensen S.C. Simonsen L.O. J. Physiol. (Lond.). 2007; 582: 1027-1036Crossref Scopus (17) Google Scholar) and swelling decreases (12Nielsen D.K. Jensen A.K. Harbak H. Christensen S.C. Simonsen L.O. J. Physiol. (Lond.). 2007; 582: 1027-1036Crossref Scopus (17) Google Scholar) the level of PIP2. Phosphatidylinositol-4-phosphate 5-kinase, which phosphorylates phosphatidylinositol 4-phosphate (11Yamamoto M. Chen M.Z. Wang Y.J. Sun H.Q. Wei Y. Martinez M. Yin H.L. J. Biol. Chem. 2006; 281: 32630-32638Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), is thought to mediate these responses. PIP2 is an excellent candidate as an upstream mediator of shrinkage-induced effects, as it can bind to and activate multiple volume-sensitive transporters (13Aharonovitz O. Zaun H.C. Balla T. York J.D. Orlowski J. Grinstein S. J. Cell Biol. 2000; 150: 213-224Crossref PubMed Scopus (176) Google Scholar, 14Rohacs T. Pfluegers Arch. 2007; 453: 753-762Crossref PubMed Scopus (77) Google Scholar). Arachidonic acid and its derivatives, generated via the cyclooxygenase and lipoxygenase pathways, have also been implicated in volume-dependent signaling (4Lambert I.H. Pedersen S.F. Poulsen K.A. Acta Physiol. (Oxf.). 2006; 187: 75-85Crossref PubMed Scopus (78) Google Scholar). Arachidonic acid is liberated from glycerophospholipids by phospholipase A2, an effect attributed variously to enhanced presentation of the phospholipid, caveolar reorganization (5Lehtonen J.Y. Kinnunen P.K. Biophys. J. 1995; 68: 1888-1894Abstract Full Text PDF PubMed Scopus (139) Google Scholar, 15Kudo I. Murakami M. Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Crossref PubMed Scopus (663) Google Scholar), activation of G-proteins (16Thoroed S.M. Lauritzen L. Lambert I.H. Hansen H.S. Hoffmann E.K. J. Membr. Biol. 1997; 160: 47-58Crossref PubMed Scopus (66) Google Scholar), increased cytosolic [Ca2+], and/or phosphorylation by mitogen-activated protein kinases (15Kudo I. Murakami M. Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Crossref PubMed Scopus (663) Google Scholar). Irrespective of the mechanism, the liberated arachidonic acid or its derivatives regulate several swelling-sensitive transport systems that catalyze the efflux of inorganic and organic osmolytes (4Lambert I.H. Pedersen S.F. Poulsen K.A. Acta Physiol. (Oxf.). 2006; 187: 75-85Crossref PubMed Scopus (78) Google Scholar, 17Meves H. Br. J. Pharmacol. 2008; 155: 4-16Crossref PubMed Scopus (122) Google Scholar). In addition, arachidonic acid can activate the NADPH oxidase that generates reactive oxygen species, which in turn regulate certain channels (18Friis M.B. Vorum K.G. Lambert I.H. Am. J. Physiol. 2008; 294: C1552-C1565Crossref PubMed Scopus (26) Google Scholar, 19Varela D. Simon F. Riveros A. Jorgensen F. Stutzin A. J. Biol. Chem. 2004; 279: 13301-13304Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). The oxidase is also activated by ceramide released by acidic sphingomyelinase, another volume-responsive lipase (7Sheikh-Hamad D. Gustin M.C. Am. J. Physiol. 2004; 287: F1102-F1110Crossref PubMed Scopus (139) Google Scholar). Intracellular Ca2+-In many cell types, swelling produces transient increases in intracellular [Ca2+]. The underlying mechanism involves opening of stretch-dependent cation channels, Ca2+ release from internal stores, and/or swelling-stimulated release of ATP, which then acts on Ca2+-mobilizing purinergic receptors in a paracrine fashion (20Okada Y. Maeno E. Shimizu T. Dezaki K. Wang J. Morishima S. J. Physiol. (Lond.). 2001; 532: 3-16Crossref Scopus (459) Google Scholar). The elevated [Ca2+] can in turn activate solute transport (see below). Protein Phosphorylation-Alterations in cell volume are associated with profound changes in protein phosphorylation. The activity of receptor and non-receptor tyrosine kinases and multiple Ser/Thr kinases is modulated by cell volume (Table 1). Volume-dependent phosphorylation is involved in (a) osmosensing (21Rosette C. Karin M. Science. 1996; 274: 1194-1197Crossref PubMed Scopus (945) Google Scholar), (b) direct regulation of channels and transporters, (c) transcription of genes encoding osmolyte-transporting systems (7Sheikh-Hamad D. Gustin M.C. Am. J. Physiol. 2004; 287: F1102-F1110Crossref PubMed Scopus (139) Google Scholar, 22Burg M.B. Ferraris J.D. Dmitrieva N.I. Physiol. Rev. 2007; 87: 1441-1474Crossref PubMed Scopus (576) Google Scholar), and (d) cytoskeletal reorganization (23Di Ciano C. Nie Z. Szaszi K. Lewis A. Uruno T. Zhan X. Rotstein O.D. Mak A. Kapus A. Am. J. Physiol. 2002; 283: C850-C865Crossref PubMed Scopus (131) Google Scholar, 24Pedersen S.F. Hoffmann E.K. Mills J.W. Comp. Biochem. Physiol. Part A Mol. Integr. Physiol. 2001; 130: 385-399Crossref PubMed Scopus (201) Google Scholar). Here, we discuss only the regulation of channels and transporters. Much of the available evidence is compiled in Table 1, but a couple of salient examples are worth highlighting. One is the Src family member Lck, which was shown to mediate the opening of swelling-activated Cl– channels (25Lepple-Wienhues A. Szabo I. Laun T. Kaba N.K. Gulbins E. Lang F. J. Cell Biol. 1998; 141: 281-286Crossref PubMed Scopus (156) Google Scholar). A second notable example is the recent realization that Ste20 (Sterile 20) family kinases (SPAK (Ste20/SPS1-related proline/alanine-rich kinase) and OSR1) and their upstream regulators, the WNK (with no K (lysine)) kinases, are the long sought-after regulators of various volume-dependent cotransporters. When activated by hyperosmolarity, WNK1 and WNK4 phosphorylate SPAK or OSR1, which in turn phosphorylates various cotransporters, thereby increasing their activity (26Delpire E. Gagnon K.B. Biochem. J. 2008; 409: 321-331Crossref PubMed Scopus (174) Google Scholar, 27Kahle K.T. Ring A.M. Lifton R.P. Annu. Rev. Physiol. 2008; 70: 329-355Crossref PubMed Scopus (202) Google Scholar). Rho Family GTPases-Rho, Rac, and Cdc42 have all been shown to respond to changes in cell size (25Lepple-Wienhues A. Szabo I. Laun T. Kaba N.K. Gulbins E. Lang F. J. Cell Biol. 1998; 141: 281-286Crossref PubMed Scopus (156) Google Scholar), and this modifies the state of actin polymerization and myosin activation (28Di Ciano-Oliveira C. Sirokmany G. Szaszi K. Arthur W.T. Masszi A. Peterson M. Rotstein O.D. Kapus A. Am. J. Physiol. 2003; 285: C555-C566Crossref PubMed Scopus (79) Google Scholar, 29Di Ciano-Oliveira C. Thirone A.C. Szaszi K. Kapus A. Acta Physiol. (Oxf.). 2006; 187: 257-272Crossref PubMed Scopus (76) Google Scholar). In addition, stimulation of Rac and Cdc42 by cell shrinkage may be at least partly responsible for the osmotically induced activation of p38 kinase (30Gagnon K.B. England R. Delpire E. Cell Physiol. Biochem. 2007; 20: 131-142Crossref PubMed Scopus (56) Google Scholar), which has been implicated in the control of ion transport. Moreover, Rho and Cdc42 are important to hypotonic stress-induced stimulation of anion efflux (31Tamma G. Procino G. Strafino A. Bononi E. Meyer G. Paulmichl M. Formoso V. Svelto M. Valenti G. Endocrinology. 2007; 148: 1118-1130Crossref PubMed Scopus (65) Google Scholar, 32Tilly B.C. Edixhoven M.J. Tertoolen L.G. Morii N. Saitoh Y. Narumiya S. de Jonge H.R. Mol. Biol. Cell. 1996; 7: 1419-1427Crossref PubMed Scopus (151) Google Scholar). As cell volume changes, transport systems on the membrane are activated. The resulting translocation of osmolytes tends to restore the original cell size. Cell shrinkage is counteracted by gain of both inorganic (mainly Na+ and Cl–) and organic solutes and the accompanying osmotically driven influx of water. This process is known as RVI. Conversely, in swollen cells, a different set of transporters is activated, leading to loss of inorganic ions (K+ and Cl–) and organic osmolytes, followed by loss of water, a process termed RVD (Fig. 1). The main solute taken up by cells to effect RVI is Na+, the major extracellular cation. Na+ is driven inwardly by the sizable concentration gradient created by the Na+/K+-ATPase (the extracellular sodium concentration is ≈140 mm, whereas the intracellular sodium concentration is <20 mm) in combination with the inward-negative membrane potential generated mainly by K+-conductive pathways. The combined electrochemical gradient is exploited by effectors to promote RVI. Na+/H+ Exchangers-In many instances, Na+ influx during RVI occurs in exchange for intracellular H+. The reaction is mediated by electroneutral antiporters, members of the NHE family. Multiple NHE isoforms have been described. NHE1, NHE2, and NHE4 are activated by osmotically induced cell shrinkage and are thus potentially involved in RVI. The ubiquitously expressed is the mechanism RVI in many cell types Grinstein S. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus Google Scholar, S. M. C. J. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). has been shown that osmotic activation of results from a in the of its S. A. S. J. Gen. Physiol. PubMed Scopus Google Scholar) and from enhanced for extracellular Na+ P.B. Am. J. Physiol. 2004; 287: Scopus Google Scholar), but the events underlying these changes are the activity of kinases is altered by cell shrinkage not alter the level of phosphorylation Grinstein S. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus Google Scholar, S. M. C. J. D. J. Biol. Chem. Full Text PDF PubMed Google Scholar). proteins that control its activity may be the of phosphorylation (Table 1). may be mechanosensitive because it was to be activated by lipids that alter membrane shape D. Hilgemann D.W. S. A. 2004; PubMed Scopus Google Scholar). Na+-K+-2Cl– many cell types, are also important to Na+ influx during RVI. to the cation that also one and isoforms M. B. Annu. Rev. Physiol. 2000; PubMed Scopus Google Scholar). and are by shrinkage M. B. Annu. Rev. Physiol. 2000; PubMed Scopus Google Scholar), and the mechanism of activation has been stimulation shrinkage direct phosphorylation (Table 1). the of inorganic ions to restore the size of cells, it the ionic concentration of the cells ionic strength the and of this is potentially to the cells and not in the long counteract this cells a response a of the of organic osmolytes M.B. Ferraris J.D. Dmitrieva N.I. Physiol. Rev. 2007; 87: 1441-1474Crossref PubMed Scopus (576) Google Scholar). the for volume in certain organic osmolytes the of As the organic osmolytes cells can to release the inorganic their ionic strength their volume in the face of The organic osmolytes are and Two mechanisms for the of organic increased from the extracellular and/or elevated of intrinsic as as and the increases their into cells (Table couple the of the organic osmolytes with the influx of Na+ and Cl– ions (Table of volume regulation Open table in a new tab the other cellular of both and challenge is due to the second mechanism, increased of the organic osmolytes in response to are at the level of transcription of the transporters or in their is by the osmotic response protein M.B. Ferraris J.D. Dmitrieva N.I. Physiol. Rev. 2007; 87: 1441-1474Crossref PubMed Scopus (576) Google Scholar), which can be activated by several of the kinases in Table are effective of volume regulation. are the main of RVI in several cell When activated, the of As a result, Na+ the cells at the as is the combined electrochemical are such that net cation by of Cl– F. H. H. E. Rev. Physiol. Biochem. Pharmacol. 2003; 148: PubMed Scopus Google Scholar). The of is not but three main can be (Table In addition to TRP channels can also promote Na+ and volume the electrochemical gradient is this ion is to net efflux of and water, leading to volume This requires efflux of a between and Cl– can be by electroneutral cotransporters, or can via pathways. of efflux by swelling has been reported in a variety of cells A. Hoffmann E.K. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus Google Scholar, F. M. F. E. H.R. T. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus (35) Google Scholar). not one but multiple channels are by swelling (Table These often in the cell and their to volume regulation has been TRP channels, which in the of RVI, have also been implicated in RVD S.F. Nilius B. Methods Enzymol. 2007; 428: 183-207Crossref PubMed Scopus (110) Google Scholar, Physiol. 2007; PubMed Scopus Google Scholar). Ca2+ cells TRP channels is thought to serve as a for activation of other channels that mediate net loss of loss of osmolytes for RVD can only the efflux of is by a anion which via Cl– is thought to be the of but the may also for at least of the efflux of organic osmolytes A. Hoffmann E.K. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus Google Scholar, I.H. 2004; PubMed Scopus Google Scholar). many the of B. G. Acta Physiol. 2003; PubMed Scopus Google Scholar). A in intracellular ionic than cell to be the sensed by B. J. T. J. G. J. Physiol. (Lond.). 1998; Scopus Google Scholar). K+-Cl– mediate electroneutral of and Cl– from swollen cells. isoforms have been to all of which are activated by swelling M. P.K. J. Membr. Biol. 2004; PubMed Scopus Google Scholar). are by of phosphorylation and which are by phosphorylation cell activate in response to and the activation is caused by This the that a set of volume-sensitive both RVI and which is increases when cells are swollen I.H. 2004; PubMed Scopus Google Scholar). The are of the intracellular F. H. H. E. Rev. Physiol. Biochem. Pharmacol. 2003; 148: PubMed Scopus Google Scholar, I.H. 2004; PubMed Scopus Google Scholar) the cell swelling. The efflux is from the in fact, more like a than a F. H. H. E. Rev. Physiol. Biochem. Pharmacol. 2003; 148: PubMed Scopus Google Scholar, I.H. 2004; PubMed Scopus Google Scholar). The of the is but was to mediate also the efflux of organic osmolytes, A. Hoffmann E.K. Acta Physiol. (Oxf.). 2006; 187: PubMed Scopus Google Scholar, I.H. 2004; PubMed Scopus Google Scholar). As was the for RVI, activation of transport during RVD a that release of organic osmolytes acts a more of swelling.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.