Experimental Physiology (1999), 84, 1023-1031 Printed in Great Britain

REVIEW ARTICLE

ICIn, AN ION CHANNEL-FORMING PROTEIN ASSOCIATED WITH CELL VOLUME REGULATION M. GSCHWENTNER, J. FURST, M. RITTER, C. BAZZINI*, E. WOLLt, A. DIENSTLt, M. JAKAB, M. KONIG, E. SCANDELLA, J. RUDZKI, G. BOTTA*, G. MEYER*, F. LANG:, P. DEETJEN AND M. PAULMICHL§ Department of Physiology, University of Innsbruck, Fritz-Pregl-StraJ3e 3, A-6020 Innsbruck, Austria, *Department of General Physiology and Biochemistry, University of Milan, Via Celoria 26, 1-20133 Milan, Italy, tDepartment of Internal Medicine, University of Innsbruck, AnichstraJ3e 35, A-6020 Innsbruck, Austria and tDepartment of Physiology, University of Tiibingen, GmelinstraJ3e 5, D-72076 Tiibingen, Germany (MANUSCRIPT RECEIVED 19 JULY 1999, ACCEPTED 9 SEPTEMBER 1999)

SUMMARY

It is not resolved whether the anionic channel involved in volume regulation after cell swelling comprises one or more subunits. Moreover, it remains to be determined which of the different proteins cloned so far, for which an involvement in cell volume regulation has been postulated, is the ideal candidate. In this review, we consider the role of the ICIn protein, cloned from MDCK cells, in cell volume regulation. INTRODUCTION

The ICln protein was originally cloned from Madin-Darby canine kidney (MDCK) cells (Paulmichl et al. 1992). The expression of this protein in Xenopus laevis oocytes generates an outwardly rectifying Cl--selective current which shows slow inactivation at depolarizing holding potentials and can be inhibited by the chloride channel blockers NPPB, DIDS and nucleotides (Paulmichl et al. 1992). Studies of the function of ICln suggest that ICln is either an ion channel itself, or a protein closely related to the ion-conducting pore. Since the ICln protein is ubiquitously expressed, the heterologous expression of ICIn in cells with an endogenous ICln homologue leads to great uncertainty about the physiological role of this protein (Clapham, 1998). Here, we briefly review the structure and function of ICIn. NOMENCLATURE

ICln (1 = current, Cl = chloride and n = nucleotide) was originally cloned from MDCK cells, and the protein and the current induced by it in oocytes were termed ICln (Paulmichl et al. 1992). Later, others referred to the ICln protein as pICIn. This caused considerable confusion because the term pICln had already been used to describe the plasmid cDNA encoding the ICln protein (Paulmichl et al. 1992). To avoid further confusion, we strongly recommend that only the term ICln is used (Alexander & Peters, 1998) and that it is specified whether the current or the protein is being referred to. The gene coding for the ICln protein was termed CLNS (CL = chloride channel and NS = nucleotide sensitive). One of the two human genes was therefore named CLNS IA, and this gene is localized on chromosome 11 and encodes § Corresponding author: markus.paulmichl@ uibk.ac.at

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Table 1. ICln identified on the mRNA level in the organs of different species (*) or cell lines (t) mRNA

Rat

Mouse

1* 14* Brain 1* 14* Lung 14 * 1* Heart 13 * Endothelial cells Blood 14* 1* Liver 1*,6*,7* It,14* Kidney 1* Adrenal gland 14 * 1* Spleen 14* 1 *t Muscle 1 Intestine 1* Uterus 14 * 1* Testis/ovary Eye Urinary bladder Whole organism

Human

3 *,

Rabbit

Bovine

8* 8* 8*

7* 7* 7 12 *

8* 8*

7* 7* 7* 7

Fish

Pig

Dog

Opossum

-

*

7t

7t

7t

-

8* 5t

7 7* 7*

2*

-

*,9 -

7*

10*

Species: 1, Abe et al. (1993); 2, Anguita et al. (1995); 3, Buyse et al. (1996); 4, Chen et al. (1999); 5, Hagos et al. (1999); 6, Huber et al. (1998); 7, Ishibashi et al. (1993); 8, Okada et al. (1995); 9, Reeves et al. (1998; ); 10, Schmarda et al. (1997); 11, Schwarz et al. (1997); 12, Szucs et al. (1996); 13, Weikersthal et al. (1999); 14, Wickman et al. (1997). Cell lines: 1, Abe et al. (1993), mouse TKC2 cells, rat A7r5 cells; 5, Hagos et al. (1999), HT29 cells; 7, Ishibashi et al. (1993), pig LLCPK I cells, dog MDCK cells; opossum OK cells.

ICln (Nagl et al. 1996). The intronless ICln gene, CLNS1B, which is localized on chromosome 6 is most probably a pseudogene (http://www.gene.ucl.ac.uk/nomenclature/; Nagl et al. 1998). THE HUMAN AND MOUSE GENES ENCODING ICIn

Fluorescence in situ hybridization (FISH) experiments revealed that parts of the human ICln sequence are present on chromosomes 11 and 6. The screening of human genomic DNA libraries made it possible to determine the exact sequence of both genes. These experiments revealed that the gene on chromosome 6 (position p12, Nagl et al. 1998) was most probably a pseudogene, since the nucleotide sequence was not identical to the cDNA sequences identified for human ICIn. This gene was termed CLNS 1 B. In contrast, the gene localized on chromosome 11 (position q13.5-14.1; NagI et al. 1996, 1998; Schwarz et al. 1997) is the gene coding for the human ICln. This gene consists of six exons and five introns resulting in a final open reading frame (ORF) comprised of 71 1 nucleotides. The mouse genes encoding ICIn sequences have also been identified. The predicted pseudogene and the expressed gene were located on chromosomes 2 and 7, respectively, which correspond to the human chromosomes 6 and 11 (Wickman et al. 1997). ICIn CLONED FROM DIFFERENT ORGANISMS

lCln is highly homologous in different species. At the amino acid level, dog (MDCK) ICIn (235 amino acids (AA)) - the first to be cloned - shows 92 7 % identity with human ICln (237AA; Anguita et al. 1995; Buyse et al. 1996; Schwarz et al. 1997), 92 8% with rat

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Table 2. 1Cln identified on the protein level in the organs of different species (*) or cell lines (t) Protein

Rabbit

Brain Heart Endothelial cells Kidney Oocyte Blood Smooth muscle Fibroblast Lung Connective tissue Uterus

Rat

Bovine

2t,8t 6*,7*

-

Pig

Dog

Xenopus laevis Monkey

-

It -

Mouse

4* 4*

t

9* -

Human

It

5*t. 6*, 10* 4t

It 1 *,4 *, 11* It

it It -

I t, 3 t It

It It

Species: 1, Buyse et al. (1996); 2, Emma et al. (1998); 3, Gschwentner et al. (1995); 4, Krapivinsky et al. (1994); 5, Laich et al. (1996); 6, Laich et al. (1997); 6, Musch et al. (1997); 7, Musch et al. (1998); 8, Sanchez-Olea et al. (1998); 9, Szucs et al. (1996); 10, Tao et al. (1998); 11, Voets et al. (1998). Cell lines: 1, Buyse et al. (1996); 2, Emma et al. (1998), C6 glioma cells; 3, Gschwentner et al. (1995), NIH 3T3; 5, Laich et al. (1996) LLCPK 1 cells; 8, Sanchez-Olea et al. (1998) C6 glioma cells.

kidney ICln (235AA; Abe et al. 1993), 92.4 % with the rat atrium Cin (240AA; Krapivinsky et al. 1994), 94-1 % with rabbit heart ICln (236AA; Okada et al. 1995), 74 % with Xenopus laevis ICln (241AA; Krapivinsky et al. 1994), and 70% with zebra fish ICln (249AA; Schmarda et al. 1997). TISSUE DISTRIBUTION OF ICin

The presence of the ICln protein or mRNA was demonstrated in several species and in a large number of different organs and cell lines (Tables 1 and 2). ICln homologues can be identified throughout evolution, from nematodes to humans (E. Scandella & M. Paulmichl, unpublished results). In organisms in which ICIn protein has been demonstrated, there is no cell type that lacks the protein. The ubiquitous presence of the ICln protein suggests that this protein is crucial for cell homeostasis. Indeed, the blocking of cell swelling-dependent anion channels prevents cell division (Voets et al. 1995). EFFECT OF VOLUME STRESS ON THE CELLULAR DISTRIBUTION OF ICIn

In cells that do not experience volume stress, the majority of the ICln protein is found in the cytosol, and only a small fraction is associated closely with the plasma membrane. Krapivinsky et al. demonstrated that in MDCK cells, in the absence of volume stress, about 70-80 % of ICln protein was localized to the cytosol, 15-20 % was localized to the nuclei, and only 5 % was found in the microsomal membrane fraction. Immunohistochemistry revealed that a small fraction of the ICln protein was present in the cell membrane (Krapivinsky et al. 1994) of these cells. The nuclear localization of the ICln protein in MDCK cells was made using a polyclonal antibody raised against a ,-galactosidase-lCln fusion protein. However, using antibodies raised against a peptide comprising the last 20 amino acids of ICln, no nuclear staining was observed in either proximal tubular cells (Laich et al. 1996), Henle's ascending limb (Tao et al. 1998b) or distal tubules of the kidney (Laich et al. 1996; Tao et al.

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N1. IGSCHWL.NT\NELR \ND O I IILRS

100 ms

Fi

o \ tes le.adS to .111Oi ltxWaCtIV edtti'n'gII Ciri-elit, xxwhich InactivIteS atI in I otein expitesed ip \Xeuop sl Is ()OL I. heI pC '\lIhc rccnidingll" WIS 111a1nLISding ,I tw-clxcctrode vonit ago claimip (T1EC) 1) and a1 potentiails iiilOte positix e than +4-m)V. V

(ltaloc stepl piotocol

as

iltidcaltcdl

1998b). Therelore, it is possible thiat the nuclearl- stalining observed in MDCK cells by KrLipiv iiisky ct cil. is the result of ain uispecific cross-rie.ction of the atntibodies used (KraLi\ivinsky ct tcl. 1994). In rlat neonataLl myocytes, a1bout 9()'Y, Of the ICln pr-otein \x as identifiedl in the cy tosolic tralction ancd 1M0Cin the meimbr-aine fra.ction. However, trnisferr-ing the cells inito a1 hlypotonic solutioin shifts a1 significait alilloulnt (aIpproximiatecly 50 ') of the 1Cmll protein to the memihbriLne fraLction. Moreover, returninhg the cellIs to the isotonic milediulIl shifts the ICIln protein bhack to the cy tosolic Fratction (Muschi et al. 1997, 1998). The durltiol of the Volum11e stless altppears to be crucial, since exposure of the cells to aL hypotonic mediuim for onily a fUew m1inLutes does inot result in alsiguificait redistlributioll of ICIIl in C6 glioma1 atnd EAhy9'26 endothelial cells (BUy se et cl. 1997; Emmima et Cll. I 998ci). EXPRESSION OF ICnI, IN DIFFERENT CELI SNYSTEMS

Expression of' IC'Iin from diflerent species including1 Cdog (PamLIIichil et al. 1992), rait (Abe et al. 1 99 3; PlAtel et al. 1 998), raibbit (OLkatd et al. 1 995; Chen et cil. 1998) 0o humalinIas (Voets et al. 1 996) in Xe opus ocytes egenrrytcs e s imilaraltl- C inrents, 'Lil shoWill (utward i rectificaition, inactivattion aLt holding potentials imorel positiv e than +40 imiV (Fig. 1), sensitivity to clhlor-ide channel blockers aid similair permeabil ities to difLre-clit Alnliolns. The complaIrison of humin ICln expressed in oocN tes with the endoglenous firog ICIn rev eals some minlor dlifler-cinces in the biophysical behaxviour, at finding that is not too sUplrisilng gi en the ftLtct thalt their amino acid sequenlces are not idlenitical (Voets et cil. 1996). The Currenit elicited in oocy tes after the expirssioni of the ICIn Protein hals sexeral t`ettures in commilloll x ith sxx ellillndclpedent atIlln0I channels chlaracteriied in num,erluS cell ty pes (OGkada, 199)7), i.e. the Iecct ion, sensitix ities to chilori de channel blockers and inacti ati at posit ix e holdin potentials. Moreoxer, it hais beeni shoxw n th.at baLcterial expressing ICIn are highly tolerant to hx potollic stress (Taio ct Cl. I 998ca). It h.as proxven xrN dificult to deter-miline the role of ICIn in

cel xVolum1Ce regUlttioln beCaCuSC SxCxellingdp-CICIeCndet chllol-idle chlAnnels arl-e ubiLlitotUSly

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extracellular

V

\ membrane

intracellular NH2 COOH Fig. 2. Cartoon showing the putative structural model of the ICIn pore protein. Only the membrane spanning section of the protein is given in detail. The N-terminal and C-terminal ends are not shown in detail but scaled down proportionally.

expressed, and no cell has been identified so far that lacks such channels. Accordingly, the Xenopus laevis homologue of dog ICln was cloned (Krapivinsky et al. 1994), which, of course, excluded a detailed characterization of the role of ICln in regulatory volume decrease (RVD) after expressing the protein in oocytes and expanding their volume. It must be assumed that such a manoeuvre would always lead to the activation of the endogenous ICln. The only feasible strategy to determine a possible role of ICln in RVD was therefore to knock down the endogenous ICln in cells with the aid of specific 'probes'. Krapivinsky et al. used monoclonal antibodies directed against a GST-ICln fusion protein and succeeded in decreasing the endogenous swelling-induced chloride current in Xenopus oocytes (Krapivinsky et al. 1994). Surprisingly, however, the decrease of ICIn current occurred 22-24 h after injecting oocytes with antibodies (Krapivinsky et al. 1994). This finding is unexpected because specific antibodies have a rather high affinity for their epitopes. An alternative approach for knocking down expression of the endogenous ICln protein is to use antisense oligodeoxynucleotides directed against ICln mRNA. In mouse NIH-3T3 fibroblasts (Gschwentner et al. 1995) and in non-pigmented bovine ciliary epithelial cells (Chen et al. 1999) the use of antisenseoligodeoxynucleotides produced a significant reduction of the swelling-induced anion current and the ICIn protein after cell swelling. These experiments establish a close connection between ICln and swelling-dependent chloride channels. Nonetheless, the crucial question of whether ICln is the ion-conducting pore remained unsolved. Indirect evidence supporting the hypothesis that ICln is the channel protein was provided by mutation experiments using the MDCK ICln protein. Wild-type MDCK ICln can be blocked by extracellular nucleotides, and mutation of a putative nucleotide binding site on the extracellular side of the ICln channel protein abolished this effect (Paulmichl et al. 1992). Furthermore, the expression of the mutated ICln protein gave rise to a current that showed altered gating behaviour compared to wild-type ICln (Paulmichl et al. 1992). The simplest explanation of these findings is that the

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M. GSCHWENTNER AND OTHERS

ICln protein may contribute to the ion-conducting pore of swelling-activated Cl- channels. However, Voets et al. failed to reproduce these results using a mutant form of rat ICln expressed in oocytes (Voets et al. 1998). Experiments in which the purified protein was functionally reconstituted in lipid bilayers definitively proved that the ICln protein can form an ion-conducting pore. The putative structural model of ICln incorporated in the cell membrane is given in Fig. 2. The relative permeability (Pcation/panion) of the reconstituted channels is dependent on the presence of calcium in the solution (Li et al. 1998; J. Furst & M. Paulmichl, unpublished results). Importantly, the current rectifies and can be blocked by nucleotides. Mutating the putative binding site for the nucleotides again leads to a dramatic reduction of the sensitivity for nucleotides, thus supporting our experiments on expression of ICln in oocytes. These experiments established that ICln can form an ion-conducting channel. However, it remains possible that the functional channels involved in RVD in native cells are built from heteromultimers (Gschwentner et al. 1998). POSSIBLE INTERACTION OF ICln WITH OTHER PROTEINS

Immunoprecipitation experiments suggested that ICln may interact with other proteins. The first protein to be identified was actin, with a molecular mass of 43 kDa (Krapivinsky et al. 1994; Schwarz et al. 1997). Subsequently, a 72 kDa protein was shown to bind ICln, which corresponds to the mammalian homologue of the yeast Skbl protein (Krapivinsky et al. 1998). To date the functional relevance of these interactions is unclear. Other proteins that may interact with ICln include the myosin light chain protein (molecular weight 17 kDa) (SanchezOlea et al. 1997; Emma et al. 1998a,b) and the 30 kDa domain of the 4.1 protein in red blood cells (Tang & Tang, 1998), as well as other unidentified proteins with varying molecular sizes (Krapivinsky et al. 1994; Tao et al. 1998b). Recently, Pu et al. (1999) have demonstrated a possible interaction of ICln with small nuclear ribonucleoproteins. However, for none of the proteins mentioned has a functional interaction with ICln been demonstrated under native conditions. Moreover, it remains to be seen for which of the putative partners a physiological role can be established. PHOSPHORYLATION OF THE

1Cln PROTEIN

Little is known about the regulation of ICln under physiological conditions. Because protein phosphorylation regulates swelling-dependent anion channels (Okada, 1997), the question of whether ICIn can be modified by kinases is of utmost importance. It has been shown that two putative tyrosine kinase phosphorylation sites are present on MDCK, rabbit and rat ICIn protein (Okada et al. 1995). Strange and co-workers (Sanchez-Olea et al. 1998) found that ICln is constitutively phosphorylated, primarily on serine residues. Li et al. (1998) have recently demonstrated that the single channel open probability of reconstituted ICIn can be decreased by casein kinase II. Moreover, ICIn has consensus phosphorylation sites for the protein kinases PKA, PKC, PKG, CKI and CKII (Sanchez-Olea et al. 1998). Additional experiments will need to be performed to understand better the regulation of ICIn by phosphorylation. CONCLUS ION

The data reviewed above suggest that ICln is a strong candidate for the anionic channel involved in volume regulation after cell swelling. However, it is clear that ICln does not act

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alone. Therefore, further research is required to elucidate the mechanisms of cell volume regulation after cell swelling. Expert technical assistance by E. Papp, and A. Wimmer is gratefully acknowledged. This work was supported in part by grants from the Austrian Science Foundation (FWF), the Union Bank of Switzerland, the Austrian National Bank, the Gastein Foundation, BIOMED, EMBO-fellowship and the Rockefeller Foundation to M.P. REFERENCES

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LAICH, A., FORST, J., NAGL, 0. U., GSCHWENTNER, M. & PAULMICHL, M. (1996). The transposition of the swelling-dependent chloride channel ICmn from the cytosol to the membrane is regulated by the cell volume. Journal of General Physiology 108, 24a.

LAICH, A., GSCHWENTNER, M., KRICK, W., NAGL, 0. U., FURST, J., HOFER, S., SUSANNA, A., SCHMARDA, A., DEETJEN, P., BURCKHARDT, G. & PAULMICHL, M. (1997). ICln, a chloride channel cloned from kidney cells, is activated during regulatory volume decrease. Kidney International 51, 477-478. Li, C., BRETON, S., MORRISON, R., CANNON, C. L., EMMA, F., SANCHEZ-OLEA, R., BEAR, C. & STRANGE, K. (1998). Recombinant pICIn forms highly cation-selective channels when reconstituted into artificial and biological membranes. Journal of General Physiology 112, 727-736. MUSCH, M. W., DAVIS-AMARAL, E. M., VANDENBURGH, H. H. & GOLDSTEIN, L. (1998). Hypotonicity stimulates translocation of ICln in neonatal rat cardiac myocytes. Pfluigers Archiv 436, 415-422. MUSCH, M. W., LUER, C. A., DAVIS-AMARAL, E. M. & GOLDSTEIN, L. (1997). Hypotonic stress induces translocation of the osmolyte channel protein pICln in embryonic skate (Raja eglanteria) heart. Journal of Experimental Zoology 277, 460-463. NAGL, 0. U., ERDL, M., SCHMARDA, A., SERI, M., PINGGERA, M. G.. GSCHWENTNER, M., DUBA, C., Luis, G. J. V., DEETJEN, P., UTERMANN, G. & PAULMICHL, M. (1996). Chromosomal localization of the gene coding for the swelling-dependent chloride channel ICIn. Genomics 38, 438-441. NAGL, U., ERDEL, M., BERGMANN, F., OEHL, B., SCANDELLA, E., MUSANTE, L., GALIETTA, L. J. V., GSCHWENTNER, M., FURST, J., SCHMARDA, A., HOFER, S., UTERMANN, G., DEETJEN, P. & PAULMICHL, M. (1998). Characterization of the human gene coding for the swelling-dependent chloride channel (CLNS lA) and further characterization of the chromosome 6 (CLNS 1 B) I ICIn at position 1 ql3.5-14.1 localization. Gene 209, 59-63. OKADA, H., ISHII, K., NUNOKI, K. & TAIRA, N. (1995). Cloning of a swelling-induced chloride current related protein from rabbit heart. Biochimica et Biophysica Acta 1234, 145-148. OKADA, Y. (1997). Volume expansion-sensing outward-rectifying Cl- channel: fresh start to the molecular identity and volume sensor. American Journal of Physiology 273, C755-789. PATEL, A. J., LAURITZEN, I., LAZDUNSKI, M. & HONORE, E. (1998). Disruption of mitochondrial respiration inhibits volume-regulated anion channels and provokes neuronal cell swelling. Journal of Neuroscience 18, 3117-3123. PAULMICHL, M., Li, Y., WICKMANN, K., ACKERMAN, M., PERALTA, E. & CLAPHAM, D. (1992). New mammalian chloride channel identified by expression cloning. Nature 356, 238-241. Pu, W. T., KRAPIVINSKY, G. B., KRAPIVINSKY, L. & CLAPHAM, D. E. (1999). pICln inhibits snRNP biogenesis by binding core spliceosomal proteins. Molecular and Cellular Biology 19, 4113-4120. REEVES, R. E., SANCHES-TORRES, J., COCA-PRADOS, M. & CAMMARATA, P. R. (1998). Expression of pI(Cln) mRNA in cultured bovine lens epithelial cells: response to changes in cell volume. Current Eye Research 17, 861-869. SANCHEZ-OLEA, R., COGHLAN, M. & STRANGE, K. (1997). ICln binds selectively to myosin light chain and a protein kinase. Biophysical Journal 72, A3. SANCHEZ-OLEA, R., EMMA, F., COGHLAN, M. & STRANGE, K. (1998). Characterization of pICln phosphorylation state and pICln-associated protein kinase. Biochimica et Biophysica Acta 1381, 49-60. SCHMARDA, A., NAGL, U., GSCHWENTNER, M., FURST, J., HOFER, S., DEETJEN, P. & PAULMICHL, M. (1997). Cloning of the swelling-dependent chloride channel ICIn homologue from zebra fish. Cell Physiology and Biochemistry 7, 298-302. SCHWARZ, R. S., RYBICKI, A. C. & NAGEL, R. L. (1997). Molecular cloning and expression of a chloride channel-associated protein pICIn in human young red blood cells: association with actin. Biochemical Journal 327, 609-616. SzUCS, G., BUYSE, G., EGGMONT, J., DROOGMANS, G. & NILIUS, B. (1996). Characterization of volumeactivated chloride currents in endothelial cells from bovine pulmonary artery. Journal of Membrane Biology 149, 189-197. TANG, C.-J. C. & TANG, T. K. (1998). The 30-kD Domain of protein 4.1 mediates its binding to the carboxyl terminus of pICIn, a protein involved in cellular volume regulation. Blood 92, 1442-1447. TAO, G.-Z., KOBAYASHI, A., ITOH, H. & TASHIMA, Y. (1998a). Expression of pICln in Escherichia coli gives a strong tolerance to hypotonic stress. FEBS Letters 434, 28-32. TAO, G.-Z., KOMATSUDA, A. MIURA, A. B., KOBAYASHI, A., ITOH, H. & TASHIMA, Y. (1998b). pICln predominantely localizes at luminal surface membranes of distal tubules and Henle's ascending limbs. Biochemical and Biophysical Research Communications 247, 668-673.

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ICln AND CELL VOLUME REGULATION

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VOETS, T., BUYSE, G., DROOGMANS, G., EGGERMONT, J. & NILIus, B. (1998). The GxGxG motif in the pICIn protein is not important for the nucleotide sensitivity of the pICln-induced Cl- current in Xenopus oocytes. FEBS Letters 426, 171-173. VOETS, T., BUYSE, G., TYTGAT, J., DROOGMANS, G., EGGERMONT, J. & NILIUS, B. (1996). The chloride current induced by expression of the protein pICln in Xenopus oocytes differs from the endogenous volume-sensitive chloride current. Journal of Physiology 495, 441-447. VOETS, T., SzUcs, G., DROOGMANS, G. & NILIUS, B. (1995). Blockers of volume-activated Cl currents inhibit endothelial cell proliferation. Pfluigers Archiv 431, 132-134. WEIKERSTHAL, S. F., BARRAND, M. A. & HLADKY, S. B. (1999). Functional and molecular characterization of a volume-sensitive chloride current in rat brain endothelial cells. Journal of Physiology 516, 75-84. WICKMAN, K., SELDIN, M. F., JAMES, M. R., GENDLER, S. J. & CLAPHAM, D. E. (1997). Partial structure, chromosomal localization, and expression of the mouse ICln gene. Genomics 40, 402-408.

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REVIEW ARTICLE ICIn, AN ION CHANNEL-FORMING ...

The gene coding for the ICln proteinwas termed. CLNS (CL .... 1), sensitivity to clhlor-ide channel blockers aid similair permeabil itiesto difLre-clit Alnliolns.

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