Physiologisches Institut, D-97070 Würzburg, Germany
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ABSTRACT |
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Cell migration plays a central role in many physiological and pathophysiological processes, such as embryogenesis, immune defense, wound healing, or the formation of tumor metastases. Detailed models have been developed that describe cytoskeletal mechanisms of cell migration. However, evidence is emerging that ion channels and transporters also play an important role in cell migration. The purpose of this review is to examine the function and subcellular distribution of ion channels and transporters in cell migration. Topics covered will be a brief overview of cytoskeletal mechanisms of migration, the role of ion channels and transporters involved in cell migration, and ways by which a polarized distribution of ion channels and transporters can be achieved in migrating cells. Moreover, a model is proposed that combines ion transport with cytoskeletal mechanisms of migration.
cytoskeleton; cell volume; sorting
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INTRODUCTION |
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CELL MIGRATION PLAYS A PIVOTAL role in many physiological and pathophysiological processes during the entire lifespan. Cell migration begins during embryogenesis, long before birth. For example, neural crest cells are migrating through the embryo to form the nervous system (48). Neuroblasts are moving within the central nervous system even after birth to reach their final place of work (47). Leukocytes are chasing invading bacteria or other pathogens, or they are "crawling" into sites of inflammation. Fibroblasts are migrating into a wound, thereby contributing to its closure (41). Migration of epithelial cells constitutes a rapid repair mechanism when gaps in an epithelial layer are to be closed. Such "epithelial wounds" frequently occur in the gastrointestinal (3) or the respiratory tract (110), or after acute renal failure (39, 98). Angiogenesis requires migration of endothelial cells (18). Finally, cell migration contributes to disease states that may be responsible for terminating life. For instance, atherosclerosis involves migration of smooth muscle cells (82), and tumor cell migration is one of the crucial steps in the metastatic cascade (33).
Despite these differences in function, all migrating cells share many similarities. Their polarization within the plane of movement along a front-rear axis is one of their most characteristic properties (67, 83). One can easily distinguish front and rear ends. When cells are crawling over a two-dimensional surface, the front is formed by a flat (~300-nm-thin), organelle-free, fanlike process, the so-called "lamellipodium," or by filopodia, which are pointed protrusions. The rear end is formed by the prominent cell body, which extends into a uropod (1, 38). The ability to establish and to maintain such a polarized state is the basis for migration. Then, repeated cycles of protrusion of the lamellipodium and retraction of the rear end of a migrating cell will result in its directional displacement. The morphological polarization of a migrating cell is highly dynamic, and external cues can lead to a rapid reorientation. For example, granulocytes change their direction of migration by 180° within a few minutes when the concentration of the chemoattractant N-formylmethionyl-leucyl-phenylalanine is reduced (2). They do so by either dissolving their original lamellipodium and forming a new one at the opposite cell pole or by making a "U-turn." Because neutrophils can be forced repetitively to flip their axis of polarization by 180°, it was speculated that they can "remember" their previous direction of locomotion (2).
Migrating cells share the ability to generate functionally distinct domains with epithelial cells and nerve cells whereby "apical" and "basolateral" membrane domains or dendrites and axons, respectively, can be distinguished (5, 40, 79, 107). However, the morphological polarization of epithelial and nerve cells is much more rigid than that of migrating cells, which need a high degree of flexibility when they encounter different extracellular cues while "en route." Thus migrating cells have no tight junction-like structures that separate apical and basolateral membrane from each other in epithelial cells (14). It is also not known whether there is a diffusion barrier separating the plasma membrane of cell body and lamellipodium. Such a diffusion barrier was shown in nerve cells whereby it limits the diffusion of axonal membrane proteins out of the axon (106). Nonetheless, recent studies indicate that some of the mechanisms underlying the polarization of migrating cells and of epithelial cells follow similar principles. This review will focus on one particular aspect of the polarization of migrating cells: the differential function and distribution of ion channels and ion transporters in migrating cells. To provide a framework for the role of ion channels and transporters in cell migration, a brief overview will be given first of those cytoskeletal mechanisms that potentially interact or act in concert with ion transport during locomotion.
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CYTOSKELETAL MECHANISMS OF CELL MIGRATION |
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Cytoskeletal mechanisms of migration have been studied in great detail (see Refs. 50 and 63 for reviews). Different cytoskeletal mechanisms take place at the front and at the rear of migrating cells to allow efficient locomotion. Actin filaments play a central role in cell migration (63). They form a dense meshwork in the lamellipodium (96). Actin filaments grow in the direction of locomotion at the leading edge of the lamellipodium (103) and thereby drive the protrusion of this cell pole (64). Actin filaments interact with a great variety of other proteins that are important for their polymerization, dynamic turnover, and structural organization into a cross-linked network (50, 63). The retraction of the rear end of a migrating cell is thought to be related to the contraction of the cortical actomyosin network underneath the cell membrane. This view is supported, among other things, by the finding that myosin II is found predominantly at the rear end of some migrating cells (15).
The functional polarization of cytoskeletal mechanisms is also maintained by a gradient of the intracellular Ca2+ concentration ([Ca2+]i), with [Ca2+]i being higher at the rear end than in the lamellipodium (12, 27, 28, 31, 87). High [Ca2+]i in the rear promotes the retraction of the rear part of a migrating cell. In contrast, low [Ca2+]i in the front will favor the protrusion of the lamellipodium (15). This spatial component of Ca2+ signaling on the intracellular "migration machinery" has superimposed on it a temporal component involving fluctuations in [Ca2+]i in migrating cells (27, 47, 52, 56, 57, 59, 87). Thus the alternating predominance of mechanisms leading to the retraction of the rear part or to the protrusion of the lamellipodium appears to be necessary for optimal cell locomotion.
The cytoskeleton can only translocate a cell when the forces generated by the cellular migration machinery are transmitted to the surrounding extracellular matrix. When there is too little friction and cells can form no contacts with their substratum, locomotion is impaired. Similarly, locomotion is also impaired when the substratum is too "sticky" and cells cannot release their contacts. Thus the interaction between the extracellular matrix and cell adhesion receptors has to be a highly coordinated process (37). It depends on the concentration of extracellular matrix proteins and the expression level of integrins, the cellular adhesion receptors (71). Moreover, the matrix contacts are dynamic and asymmetric. Thus a migrating cell forms new contacts at its front, and contacts are released at its rear part through Ca2+-dependent phosphatases (34). Integrins are brought back to the cell front by oriented endocytic recycling (24, 73). Depending on the adhesiveness of the substrate, integrins can also be left behind (shed), so that one can visualize a cell's path retrospectively (25, 70).
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ION CHANNELS AND TRANSPORTERS MODULATE CELL MIGRATION |
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General Considerations
The function of ion channels and transporters is closely related to the actin cytoskeleton. On one hand, ion channels and transporters can be regulated by the state of actin filaments (60, 62). Thus the ability of shrunk or swollen cells to restore their normal volume by means of activating ion channels and transporters is impaired when normal actin filament turnover is disturbed by drugs such as cytochalasin (49). In addition, the organization of the actin filament network by accessory proteins also modulates the ability of a cell to regulate its volume (13). On the other hand, changes in cell volume themselves in turn influence the actin cytoskeleton. Such volume changes can be elicited by activating or inhibiting ion channels and transporters or by treating cells with anisosmotic solutions. Cell swelling is accompanied by a disintegration of actin filaments, and cell shrinkage is followed by an assembly of actin filaments (32, 91). This mutual dependence of actin filaments and cell volume indicates that the "correct" cell volume and thereby the correct activity of ion channels and transporters must play an important role in cell migration, a process critically relying on a rapid turnover of actin filaments (63). By setting the correct cell volume, ion channels and transporters create the intracellular milieu that is required for the optimal operation of the cytoskeletal migration machinery. Thus it is not surprising that migration of a number of cell types is modulated by the activity of ion channels and transporters.Ion Channels Required for Cell Migration
Human melanoma cells, which lack the actin cross-linking protein ABP-280, are unable to migrate (17). Interestingly, they are also unable to activate K+ channels appropriately during volume regulation. Both defects are "rescued" by transfecting these cells with ABP-280 (13, 17). However, migration of these rescued melanoma cells is impaired when Ca2+-sensitive K+ channels (IK1) are blocked (90). This type of K+ channel is required for migration of other cell types, too (80, 90, 93). Thus IK1 channel activity appears to be a general requirement for cell migration. Accordingly, IK1 channels are predominantly found in cells with the ability to migrate. Voltage-dependent K+ channels (Kv1.3 and Kv3.1) have been related to migration of lymphocytes (54) and of embryonic nerve cells (35). The outgrowth of neurites, a process resembling the protrusion of lamellipodia, is also modulated by the activity of K+ channels (4). Migration of granular cells from the cerebellum depends on the activity of N-type Ca2+ channels and N-methyl-D-aspartate receptors (45, 46). Stretch-activated, Ca2+-permeable nonselective cation channels are involved in migration of fish epithelial keratocytes (52). Locomotion of glioma cells (97) and of transformed renal epithelial (MDCK-F) cells (68) is regulated by the activity of ClFunctional Polarization of Ion Channels in Migrating Cells
As mentioned above, ion channels and transporters have a great impact on cell volume. By mediating salt efflux or influx, followed by osmotic water flux, they elicit cell shrinkage or cell swelling. This implies that changing the activity of ion channels or transporters in migrating cells will have an effect on their volume. These considerations apply in particular to Ca2+-sensitive IK1 channels, which are intermittently activated in migrating cells by fluctuations in [Ca2+]i (26, 92, 93). Studies on volume regulation show that activation of these K+ channels results in cell shrinkage (49). Such volume loss due to activation of IK1 channels also occurs in migrating cells. Oscillations in [Ca2+]i trigger a massive intermittent loss of cellular K+ (19, 88) and a loss of up to 20% of the volume of MDCK-F cells (85). Because blockade of IK1 channels inhibits migration, we postulated that K+ channel-mediated volume fluctuations are part of or modulate the cellular migration machinery. In a similar way, a ClHowever, to contribute to cell migration, such cell volume changes
should optimally be polarized within the cell. This should be reflected
by a polarized distribution of the respective channel or transporter
activity in migrating cells. This hypothesis can be tested by topically
applying appropriate blockers to either the front or the rear part of
migrating cells. Indeed, inhibition of IK1 channels at the rear and
front of migrating MDCK-F cells has differential effects on migration.
Cells are only slowed down when the rear part of a crawling cell is
exposed to the scorpion venom charybdotoxin, a blocker of IK1 channels
(88). When applied to the lamellipodium, charybdotoxin has
no effect on migration. Consequently, IK1 channel-mediated volume
changes almost exclusively affect the rear part of migrating cells
(85). Thus IK1 channels facilitate the retraction of the
rear part of migrating cells by inducing a local cell shrinkage at this
cell pole. So far it is not known whether Cl channel
activity is also polarized in migrating cells.
Ion Transporters Required for Cell Migration
Ion transporters play an important role in cell migration, too. The Na+/H+ exchanger (NHE1) is the best studied transporter in this context. It is a member of a gene family consisting of at least six isoforms, NHE1-NHE6 (16). The major functions of the ubiquitously expressed "housekeeping" isoform NHE1 are regulation of intracellular pH and of cell volume. However, it is also involved in cell migration. It is activated on chemotactic stimulation of neutrophil granulocytes, thereby increasing their cell volume and facilitating their migratory response (78, 81, 95). NHE activity is also required for migration of keratinocytes (6), human melanoma, and MDCK-F cells, whereby it operates in parallel with the anion exchanger AE2 and the Na+-HCOFunctional Polarization of Ion Transporters in Migrating Cells
If retraction of the rear part of migrating cells involves local cell shrinkage, one might anticipate that local cell swelling at the front contributes to the protrusion of the lamellipodium. In such a scenario, the activity of transporters mediating salt and osmotically obliged water uptake (e.g., the Na+/H+ or ClModel of Ion Transport in Cell Migration
On the basis of these studies, a model was developed that describes migration as temporally and spatially separated phases of local cell swelling and cell shrinkage. We proposed the following cycle of events by which polarized activity of ion channels and transporters contributes to cell migration (91; see Fig. 1). When [Ca2+]i is at its resting level, IK1 channel activity is minimal. Cell volume is gradually increased, among other things, by the parallel operation of Na+/H+ and Cl
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Although there is experimental evidence supporting this model, that ion channels and transporters modulate cell migration by additional mechanisms as well cannot be ruled out. For example, the rise of [Ca2+]i after stimulation of neutrophil granulocytes is attenuated by a depolarization of the membrane potential (20). Accordingly, it has been shown in a neutrophil cell line (HL-60) that the IK1 channel blocker clotrimazole decreases Ca2+ influx (44). Hence, it is conceivable that IK1 channel blockade impairs migration not only by preventing fluctuations of the cell volume but also by altering the intracellular Ca2+ homeostasis. This could impair migration, among other things, by inhibiting Ca2+-dependent release of integrins from their substrate.
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STRUCTURAL POLARIZATION OF ION CHANNELS AND TRANSPORTERS IN MIGRATING CELLS |
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Functional polarization of ion channels or transporters in migrating cells can be achieved by either inserting them into the cell membrane in a polarized way, differentially regulating them at the front or rear part of the cell, or a combination of both. There is experimental evidence for all three possibilities.
Structural Polarization of Ion Channels
Voltage-dependent Kv1.4 channels are clustered at the leading edge of the lamellipodium when transfected into migrating cells (76). The same holds true for cloned Ca2+-sensitive IK1 channels (94). This is surprising insofar as functional experiments provided no evidence for IK1 channel activity at this cell pole (85, 88). That is, structural and functional polarization of IK1 channels in migrating cells do not match. One explanation for this discrepancy is that the functional polarization of IK1 channels is due to a differential regulation of the channel protein in the front and rear part of migrating cells. IK1 channel activity could be limited to the rear part of locomoting cells by a gradient of [Ca2+]i, the major regulator of IK1 channels, whereby it is higher than at the front (12, 27, 28, 31, 87). Regulation of IK1 channels by protein kinase C (89) could be another cause for the predominance of IK1 channel activity in the rear part of migrating cells. At least in migrating lymphocytes, protein kinase C is found preferentially in their rear part (23). Finally, the mechanical properties of the lamellipodium compared with those of the cell body could be responsible for limiting IK1 channel-mediated effects to the cell body. The lamellipodium is much stiffer than the cell body (75), and it is attached more firmly to the substratum than the cell body (85). It is therefore conceivable that the rigid actin gel and the tight adherence to the substratum prevent the lamellipodium from decreasing its volume to the same extent as the cell body.Structural Polarization of Ion Transporters
The Na+/H+ exchanger NHE1 is concentrated at the leading edge of the lamellipodium of fibroblasts, where it colocalizes with components of focal adhesion complexes (30, 74). Assuming that NHE1 is distributed in a similar way in other cells, too, the structural polarization of the protein explains the functional polarization of Na+/H+ exchange activity in migrating cells (43). Possibly, polarized Na+/H+ exchange activity is reinforced by an additional regulatory effect. NHE1 activity is involved in signaling events triggered by integrin-mediated cell adhesion, which also include RhoA- regulated cytoskeletal restructuring (100, 101). Two other transporters are also distributed in a polarized way in migrating cells: the ClMechanisms for Polarization of Ion Channels and Transporters in Migrating Cells
All ion channels and transporters, which are clustered at the leading edge of the lamellipodium of migrating cells (Kv1.4 and IK1 channels; NHE1, AE2, NBC1; see Table 1), have one property in common. They are all inserted into the basolateral membrane when expressed in polarized epithelial cells (9, 53, 84, 99, 102). By contrast, an apical K+ channel (ROMK2; 108) or an apical transporter (Na+/H+ exchanger NHE3; 102) is not concentrated at the leading edge but appears to be distributed diffusely on the cell surface (22, 104). These observations suggest that basolateral and apical transport proteins are recognized as such by migrating cells and delivered in specific ways to the cell surface. This implies the existence of basolateral and apical routes from the trans-Golgi network (TGN) to the cell surface of migrating cells. Studies with viral marker proteins of the apical and basolateral membrane lend support to this notion. Apical (influenza virus hemagglutinin) and basolateral markers (vesicular stomatitis virus G protein and Semliki Forest virus spike glycoprotein) are transported via two distinct routes from the TGN to the plasma membrane even in unpolarized cells (66, 109). These transport routes correspond to apical and basolateral routes in polarized epithelia.
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A polarized distribution of basolateral viral markers is induced by stimulating fibroblast migration (7) or by coexpression with rab8 (7). rab8 Is a small Ras-like GTPase that regulates polarized membrane transport to the basolateral membrane of epithelial cells and to dendrites in neurons (5). Basolateral membrane markers accumulate at the leading edge of motile fibroblasts or in protrusions of baby hamster kidney cells. Apical markers are apparently distributed randomly on the cell surface (72; see Table 1). These studies are important for understanding the distribution of ion channels and transporters in migrating cells. By analogy, one can hypothesize that basolateral ion channels and transporters are delivered to the leading edge of the lamellipodium by the same rab8-dependent mechanism, too. Interestingly, it was also demonstrated that expression of rab8 in formerly unpolarized cells results in the appearance of cell processes reminiscent of lamellipodia (72). Thus the delivery of membrane proteins to these processes and the development of a polarized morphology go hand in hand.
This is of particular importance for migrating cells, the polarized
morphology of which is constantly "renewed" by a process likely
involving the exocytotic insertion of membrane vesicles at the leading
edge (10, 11). As indicated in Fig.
2, these vesicles are probably derived
from two sources. One pool serves the transport of newly synthesized
basolateral membrane proteins from the TGN to the plasma membrane at
the cell front (7, 72). Moreover, such vesicles can
originate from an endocytic cycle that brings membrane proteins,
endocytosed over the cell surface, back to the cell front (10,
11, 24, 36, 51, 73). Sorting of basolateral proteins and the
endocytic cycle rely, among other things, on overlapping tyrosine- or
dileucine-based signaling sequences in the COOH termini of the
respective proteins (5, 40). We observed that IK1 channels
are no longer concentrated at the leading edge of migrating cells when
a dileucine motif in their COOH terminus is mutated (94; Schwab A, and
Schulz C, unpublished observations). Future studies will have
to show whether this is due to missorting and/or a defect in endocytic
recycling of the channel protein. Nonetheless, these observations point to the importance of basolateral sorting and/or endocytic recycling in
the maintenance of polarized ion channel distribution in migrating cells.
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There is also evidence that so-called "glycolipid rafts" are involved in the polarization of membrane proteins (e.g., chemokine receptors) in migrating breast adenocarcinoma cells (MCF-7) (58). So far, it is not known whether the association of ion channels and transporters with glycolipid rafts plays a role in their subcellular distribution in migrating cells, too. However, this study shows that multiple sorting pathways exist in locomoting cells. It remains to be elucidated whether they are cell-type specific or operating in parallel.
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PERSPECTIVES |
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Studies on the role of ion channels and ion transporters in cell
migration are in an early stage, and many questions need to be
clarified. For example, the role of ion channels and transporters in
migration of epithelial cells during the closure of epithelial lesions
has not yet been studied in detail. Initial studies indicate that these
membrane proteins, which are responsible for many of the epithelial
functions and are abundantly expressed in epithelial cells, are
utilized in this process, too (55). What are the exact
molecular mechanisms by which ion transport affects the cytoskeletal
migration machinery? How and why are some ion channels and transporters
directed to the leading edge of the lamellipodium whereas others are
not? Are PDZ-domain binding proteins involved in clustering ion
channels and transporters at the leading edge and in linking them to
the cytoskeleton? In this context, it is noteworthy that the
Na+/H+ exchanger regulatory factor (NHE-RF)
interacts with one of its two PDZ domains with members of the family of
MERM proteins (merlin, ezrin, radixin, and moesin), which function as
possible linkers between integral membrane proteins and the
cytoskeleton (105). Both NHE-RF and merlin colocalize to
membrane ruffles and filopodia (29, 65), i.e., to similar
structures as shown for several ion channels and transporters
(30, 42, 43, 76, 94). Interestingly, NHE-RF regulates
Na+-HCO
The last few years witnessed great progress in our knowledge of cell polarization. It became clear that many of the critical mechanisms have been conserved throughout the evolution from yeast to mammals, as well as in different cell types (21). This knowledge provides a framework for the development of testable hypotheses with respect to the spatial distribution of ion channels and transporters in migrating cells. In particular, the discovery that apical and basolateral sorting pathways also exist in migrating cells shows that the comparison with epithelial cells is very fruitful. Studies on ion transport and cell migration suggest that ion channels and transporters play a prominent role in this important physiological and pathophysiological process. Thereby, they can also be of potential therapeutic use in disease states in which cell migration plays a critical pathophysiological role. Finally, it is conceivable that the localization of ion channels or transporters in migrating cancer cells may be of diagnostic value. Ninety percent of malignant tumors originate from epithelial cells. Tumor formation in epithelia leads to the loss of their normal polarity along the apicobasolateral axis (86). However, cancer cells become polarized along a front-rear axis when they start to migrate to form metastases. On the basis of present knowledge, it is likely that the acquisition of a migratory phenotype leads to a characteristic redistribution of ion channels and transporters in migrating cancer cells, which might be helpful in identifying metastasizing cancer cells. Thus unraveling the mechanisms by which ion channels and transporters modulate migration and are positioned in migrating cells will be a rewarding challenge for the coming years.
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ACKNOWLEDGEMENTS |
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I thank Stefan Silbernagl and, in particular, Hans Oberleithner. Without their continuous support and friendship, much of our work on ion transport in cell migration would not have been possible. The work from my laboratory represents the combined efforts of Magnus Klein, Agnes Röll, Christoph Schulz, Barbara Schuricht, Ponke Seeger, Dietmar Weinhold, and Andrea Wulf, in collaboration with Jürgen Reinhardt and Stefan W. Schneider.
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FOOTNOTES |
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This work was supported by Deutsche Forschungsgemeinsschaft Grants SFB 176 A6 and Schw 407/7-1.
Address for reprint requests and other correspondence: A. Schwab, Physiologisches Institut, Röntgenring 9, D-97070 Würzburg, Germany (E-mail: albrecht.schwab{at}mail.uni-wuerzburg.de).
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