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PubMed1996

Chloride transport across kidney epithelia through CLC chloride channels.

This review summarizes recent progress in elucidating the chloride-transporting mechanisms in kidney epithelia, focusing particularly on those which act through the newly identified chloride channels. A family of chloride channel proteins (ClC chloride channels) consisting of at least 9 members (ClC-1, 2, 3, 4, 5, 6, 7, K1 and K2) has recently been identified in mammals. Although all of these ClC channels, except for skeletal muscle-specific ClC-1, are expressed in the kidney, only ClC-K1 and K2 are kidney-specific ClC chloride channels, suggesting that they play an important role in the kidney. The functional properties and intrarenal localization of these chloride channels are summarized, and their involvement in certain tubular dysfunctions and physiological roles are discussed in this report.

Biological Transport↗
PubMed1992

cGMP-dependent protein kinase regulation of a chloride channel in T84 cells.

Chloride channels at the apical membrane of intestinal epithelial cells are involved in the excessive fluid secretion in diarrhea and diminished secretion in cystic fibrosis (CF). Diarrhea induced by heat-stable toxin from Escherichia coli is associated with elevated guanosine 3',5'-cyclic monophosphate (cGMP) in intestinal epithelial cells, but it is unknown whether chloride secretion is regulated by cGMP directly or via cGMP-dependent protein kinase (PKG). Single-channel recordings (inside-out excised patches) from the apical membrane of T84 cells reveal a 10-pS chloride channel with a linear current-voltage relationship, which is opened when an endogenous membrane-bound PKG is activated with ATP (1 mM) and cGMP (100 microM). Soluble PKG (200 nM) isolated from bovine lung, added to the intracellular face of patches, also opens this channel. No activation occurs with Ringer solution alone or only ATP or cGMP. Addition of nonhydrolyzable forms of ATP (AMP-PNP, 1 mM) or a combination of ATP, cGMP, plus H-8 (5 microM), an inhibitor of PKG, also does not stimulate the channel. The catalytic subunit of adenosine 3',5'-cyclic mono-phosphate-dependent protein kinase (PKA, 200 nM, with 1 mM ATP) activates a channel with similar characteristics. The 10 pS channel has a PNa/PCl ratio of 0.06, an anion selectivity of Br- (1.2) greater than Cl- (1.0) greater than I- (0.8) greater than F- (0.4), and a low affinity for the chloride channel blockers, 4,4-dinitrostilbene-2,2-disulfonic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2004

A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity.

BACKGROUND: Tubular transepithelial reabsorption of chloride along the nephron is a major determinant of body salt and water homeostasis and blood pressure regulation. About 40% of the glomerulary filtered sodium chloride are reabsorbed in the distal nephrons. Vectorial transepithelial sodium chloride transport is critically dependent on the function of basolateral ClC-K type chloride channels there. Modulation of ClC-Kb chloride channel activity by polymorphic variations of the CLCNKB gene, thus, could form a molecular basis for salt sensitivity of blood pressure regulation. In this study we tested the effect of several polymorphic variants on ClC-Kb chloride channel activity. METHODS: After heterologous expression in Xenopus oocytes, ClC-Kb channel activity and surface expression in presence of the ClC-K beta subunit barttin were determined by two-electrode voltage-clamp analysis, immunofluorescence, and ClC-Kb surface enzyme-linked immunosorbent assay (ELISA). RESULTS: Chloride currents induced by the ClC-Kb variants L27R, G214A, I419V, T562M, and E578K were not significantly different from wild-type currents. The ClC-KbT481S variation, however, which showed a frequency of 20% in our control population, dramatically activated chloride conductance by a factor of 20. Activation of chloride currents was also observed after introducing homologous mutations in ClC-Ka and ClC-K1, but not in ClC-2 and ClC-5 chloride channels. ClC-Kb activation by the T481S mutation did not change intrinsic ion channel pore properties and did not require increased surface expression of ClC-KbT481S. CONCLUSION: Genetic heterogeneity of ClC-Kb chloride channels correlates with functional heterogeneity, which assigns ClC-Kb to a set of genes potentially relevant for polygenic salt-sensitivity of blood pressure regulation.

Animals↗
PubMed1991

Different types of blockers of the intermediate-conductance outwardly rectifying chloride channel in epithelia.

Epithelial chloride channels can be blocked by various inhibitors, which show considerable differences in their molecular structure. In the present patch-clamp study, we compared different blockers of one type of epithelial Cl- channel with respect to their inhibitory potency. We applied the blockers to excised inside-out-or outside-out-oriented membrane patches of cultured HT29 colon carcinoma and respiratory epithelial cells (REC) containing the outwardly rectifying intermediate-conductance (ICOR) chloride channel. Four types of inhibitory compounds were tested: stilbene disulphonate derivatives, indanyloxyacetic acid, amidine, and arylaminobenzoates. The concentrations for half-maximal inhibition (IC50) for the different channel blockers were (mumol/l): 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulphonic acid 100; 4,4'-diisothiocyanato-stilbene-2,2'-disulphonic acid 80; indanyloxyacetic acid 9; 4,4'-dinitrostilbene-2,2'-disulphonic acid 8; amidine 8 and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) 0.9. All compounds, when applied to the cytosolic side of the channel, induced a flicker-type block of the ICOR Cl- channel at lower concentrations and a complete channel inhibition at higher concentrations. The inhibitory potency of NPPB was much higher when it was added to the external surface of the channel in outside-out-oriented membrane patches. At 1 mumol/l the inhibition was complete. All blocker effects were fully reversible. The probe with the highest affinity (NPPB) and a closely related compound 5-nitro-2-(3-phenylethylamino)-benzoate (NPEB) were used to construct macromolecular probes by linking these blockers to aminopolyethyleneglycol (PEG) or amino-ethyl-O-dextran (5 kDa).2+ These macromolecular NPPB and NPEB derivatives inhibited the ICOR Cl- channels only from the outside but had no effect on the cytosolic side.(ABSTRACT TRUNCATED AT 250 WORDS)

Amidines↗
PubMed2002

ClC-5: ontogeny of an alternative chloride channel in respiratory epithelia.

Chloride transport is critical to many functions of the lung. Molecular defects in the best-known chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), lead to impaired function of airway defensins, hydration of airway surface fluid, and mucociliary clearance leading to chronic lung disease, and premature death, but do not cause defects in lung development. We examined the expression of one member of the ClC family of volume- and voltage-regulated channels using the ribonuclease protection assay and Western blot analysis in rats. ClC-5 mRNA and protein are most strongly expressed in the fetal lung, and expression is maintained although downregulated postnatally. In addition, using immunocytochemistry, we find that ClC-5 is predominantly expressed along the luminal surface of the airway epithelium, suggesting that ClC-5 may participate in lung chloride secretion. Identifying candidate genes for critical ion transport functions is essential for understanding normal lung morphogenesis and the pathophysiology of several lung diseases. In addition, the manipulation of non-CFTR chloride channels may provide a viable approach for treating cystic fibrosis lung disease.

Aging↗
PubMed1992

A ubiquitous 64-kDa protein is a component of a chloride channel of plasma and intracellular membranes.

Chloride channels are present in the plasma and intracellular membranes of most cells. Previously, using the ligand indanyloxyacetic acid (IAA), we purified four major proteins from bovine kidney cortex membrane vesicles. These proteins gave rise to chloride channel activity when reconstituted into phospholipid vesicles. Two of these proteins (97 and 27 kDa) were found to be drug-binding proteins by N-terminal sequence analysis. Antibodies raised to the 64-kDa protein stained only this protein on immunoblots, and only this protein was present after purification on an immunoaffinity column. In addition, these same antibodies were able to deplete IAA-94 inhibitable chloride channel activity from solubilized kidney membranes. Of fractions obtained from the gel filtration of solubilized kidney membranes, only those containing this 64-kDa protein exhibited measurable chloride channel activity. Immunoblots of a variety of species and cell types, both epithelial and nonepithelial, revealed that this protein is ubiquitous and highly conserved. Immunocytochemistry in CFPAC-1 cells revealed staining for this protein on the apical plasma membrane and in the membranes of intracellular organelles. These results demonstrate that the integral membrane protein p64 is a component of chloride channels present in both epithelial plasma membrane and the membranes of intracellular organelles.

Amino Acid Sequence↗
PubMed2004

Expression of novel isoforms of the CIC-1 chloride channel in astrocytic glial cells in vitro.

Chloride channels play an important role in glial astrocyte function. However, in astrocytes, no chloride channels besides the gamma-aminobutyric acid (GABA)A receptor, glycine receptor, and ClC-2 chloride channels have been molecularly identified. In this study, we examined the expression of the ClC-1 chloride channel in rat astrocytic glioma C6 cells and rat primary astrocytes. Five isoforms of ClC-1, but not skeletal muscle ClC-1 (SM ClC-1), were found to be expressed in C6 cells. Comparison with rat SM ClC-1 showed that common features shared by these isoforms are a short 3' end with a deletion of the nucleotides from 3115 to 3197 and a substitution of T by C at nucleotides 480 and 1733. Three of the five isoforms, M1, M2, and M3, were produced by partial deletion of ClC-1 exon 7, partial insertion of ClC-1 exon 7a, and a TAG insertion at nucleotide 858, respectively. One of the two remaining isoforms, M4, was produced by partial deletion of ClC-1 exon 8 at nucleotide 937; the other, M5, was the same as SM ClC-1 except for the short 3' end and substitutions at the two positions. Only the M5 isoform could be expressed as a functional channel in Xenopus oocytes. This glial isoform exhibited less dependence on voltage and extracellular Cl- than rat SM ClC-1. However, the anion selectivity sequence and the anthracene-9-carboxylic acid (9-AC) sensitivity of this channel were the same as for SM ClC-1. Since whole-cell recordings failed to detect ClC-1-like Cl- currents in C6 cells, it appears that the ClC-1 isoform is functioning in intracellular organelles. In rat primary astrocytes, we found that the M2 isoform as well as two additional distinct isoforms were expressed. The present study showed that astrocytic glial cells express multiple isoforms of the ClC-1 chloride channel, which has been thought to be expressed almost exclusively in the skeletal muscle.

Animals↗
PubMed1999

SITS blockade induces multiple subconductance states in a large conductance chloride channel.

The effect of the chloride channel blocker 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS) on the gating and amplitude of an endothelial chloride channel was explored using the outside-out configuration of the patch-clamp technique. Under control conditions the channel displayed two main gating modes: shut and fully open. Transitions to equally spaced subconductance states were rarely observed (less than 10 events/minute). At low concentrations (<45 microm), SITS increased the number of transitions to the three subconductance states in a concentration-dependent manner, while reducing the number of transitions to the fully open state. This effect was maintained after removing SITS from the bath solution, suggesting that the modifications in the channel induced by SITS were irreversible. All four conducting states had similar current-voltage relationships. At higher concentrations (>45 microm), SITS reduced the amplitude of all conducting states (three subconductances and fully open). This effect was fully reversible upon SITS removal from the bath solution. A half-inhibitory concentration (IC50) of 55.6 +/- 2.7 microm (+60 mV) and 66.7 +/- 2.2 (-60 mV) was obtained from the fitting to a Langmuir function. All these results are compatible with the existence of two SITS binding sites in the chloride channel: one of high affinity responsible for the increment in the number of transitions to subconductance states, and one low affinity binding site involved in the reduction of the amplitude of all conducting states.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed2000

The gastric H,K-ATPase blocker lansoprazole is an inhibitor of chloride channels.

1. It was postulated that swelling dependent chloride channels are involved in the proton secretion of parietal cells. Since omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are structurally related to phenol derivatives known to block swelling dependent chloride channels, we set out to test, whether these substances--which are known to block the H,K-ATPase--could also lead to an inhibition of swelling-dependent chloride channels. Swelling-dependent chloride channels--characterized in many different cell types--show highly conserved biophysical and pharmacological features, therefore we investigated the effect of omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 on swelling-dependent chloride channels elicited in fibroblasts, after the reduction of the extracellular osmolarity. 2. Omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are able to block swelling-dependent chloride channels (IClswell). 3. Lansoprazole and its protonated metabolite AG2000 act on at least two different sites of the IClswell protein: on an extracellular site which seems to be in a functional proximity to the nucleotide binding site, and on an intracellular site which allows the formation of disulfide-bridges. 4. The inhibition of the proton pump and the simultaneous blocking of chloride channels by omeprazole, lansoprazole and its acid activated sulphenamide form AG2000, as described here could be an effective mode to restrict proton secretion in parietal cells.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1987

Blockage of chloride channels by HEPES buffer.

Chloride channels of neurons of Drosophila are blocked when the cytoplasmic side of the membrane is exposed to the commonly used buffering agents 4-(2-hydroxyethyl)-1-piperazine ethanesulphonic acid (HEPES) and 4-morpholinepropanesulphonic acid (MOPS). In the presence of these compounds, chloride channels appear to function as a complex of multiple protochannels.

Animals↗
PubMed2005

Location of a common inhibitor binding site in the cytoplasmic vestibule of the cystic fibrosis transmembrane conductance regulator chloride channel pore.

Chloride transport by the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is inhibited by a broad range of organic anions that enter the channel pore from its cytoplasmic end, physically occluding the Cl- permeation pathway. These open channel blocker molecules are presumed to bind within a relatively wide pore inner vestibule that shows little discrimination between different large anions. The present study uses patch clamp recording to identify a pore-lining lysine residue, Lys-95, that acts to attract large blocker molecules into this inner vestibule. Mutations that remove the fixed positive charge associated with this amino acid residue dramatically weaken the blocking effects of five structurally unrelated open channel blockers (glibenclamide, 4,4'-dinitrostilbene-2,2'-disulfonic acid, lonidamine, 5-nitro-2-(3-phenylpropylamino)benzoic acid, and taurolithocholate-3-sulfate) when applied to the cytoplasmic face of the membrane. Mutagenesis of Lys-95 also induced amino acid side chain charge-dependent rectification of the macroscopic current-voltage relationship, consistent with the fixed positive charge on this residue normally acting to attract Cl- ions from the intracellular solution into the pore. These results identify Lys-95 as playing an important role in attracting permeant anions into the channel pore inner vestibule, probably by an electrostatic mechanism. This same electrostatic attraction mechanism also acts to attract larger anionic molecules into the relatively wide inner vestibule, where these substances bind to block Cl- permeation. Thus, structurally diverse open channel blockers of CFTR appear to share a common molecular mechanism of action that involves interaction with a positively charged amino acid side chain located in the inner vestibule of the pore.

Amino Acid Sequence↗
PubMed2003

Mutation-induced blocker permeability and multiion block of the CFTR chloride channel pore.

Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is blocked by a broad range of anions that bind tightly within the pore. Here we show that the divalent anion Pt(NO2)42- acts as an impermeant voltage-dependent blocker of the CFTR pore when added to the intracellular face of excised membrane patches. Block was of modest affinity (apparent Kd 556 microM), kinetically fast, and weakened by extracellular Cl- ions. A mutation in the pore region that alters anion selectivity, F337A, but not another mutation at the same site that has no effect on selectivity (F337Y), had a complex effect on channel block by intracellular Pt(NO2)42- ions. Relative to wild-type, block of F337A-CFTR was weakened at depolarized voltages but strengthened at hyperpolarized voltages. Current in the presence of Pt(NO2)42- increased at very negative voltages in F337A but not wild-type or F337Y, apparently due to relief of block by permeation of Pt(NO2)42- ions to the extracellular solution. This "punchthrough" was prevented by extracellular Cl- ions, reminiscent of a "lock-in" effect. Relief of block in F337A by Pt(NO2)42- permeation was only observed for blocker concentrations above 300 microM; as a result, block at very negative voltages showed an anomalous concentration dependence, with an increase in blocker concentration causing a significant weakening of block and an increase in Cl- current. We interpret this effect as reflecting concentration-dependent permeability of Pt(NO2)42- in F337A, an apparent manifestation of an anomalous mole fraction effect. We suggest that the F337A mutation allows intracellular Pt(NO2)42- to enter deeply into the CFTR pore where it interacts with multiple binding sites, and that simultaneous binding of multiple Pt(NO2)42- ions within the pore promotes their permeation to the extracellular solution.

Animals↗
PubMed2003

Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore.

Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is blocked by highly lyotropic permeant anions which bind tightly within the pore. Here we show that several different substitutions of a positively charged amino acid residue, arginine R334, in the putative outer mouth of the CFTR pore, greatly reduce the block caused by lyotropic Au(CN)2- ions applied to the intracellular side of the channel. Fixed positive charge at this site appears to play a role in Au(CN)2- binding, as judged by multiple substitutions of differently charged amino acid side chains and also by the pH dependence of block conferred by the R334H mutant. However, non-charge-dependent effects also appear to contribute to Au(CN)2- binding. Mutation of R334 also disrupts the apparent electrostatic interaction between intracellular Au(CN)2- ions and extracellular permeant anions, an interaction which normally acts to relieve channel block. All six mutations studied at R334 significantly weakened this interaction, suggesting that arginine possesses a unique ability to coordinate ion-ion interactions at this site in the pore. Our results suggest that lyotropic anions bind tightly to a site in the outer mouth of the CFTR pore that involves interaction with a fixed positive charge. Binding to this site is also involved in coordination of multiple permeant anions within the pore, suggesting that anion binding in the outer mouth of the pore is an important aspect in the normal anion permeation mechanism.

Animals↗
PubMed1997

Molecular identification of a volume-regulated chloride channel.

A volume-regulated chloride current (ICl.vol) is ubiquitously present in mammalian cells, and is required for the regulation of electrical activity, cell volume, intracellular pH, immunological responses, cell proliferation and differentiation. However, the molecule responsible for ICl.vol has yet to be determined. Although three putative chloride channel proteins expressed from cloned genes (P-glycoprotein, pICln and ClC-2 ) have been proposed to be the molecular equivalent of ICl.vol, neither P-glycoprotein nor pICln is thought to be a chloride channel or part thereof, and the properties of expressed ClC-2 channels differ from native ICl.vol. Here we report that functional expression in NIH/3T3 cells of a cardiac clone of another member of the ClC family, ClC-3, results in a large basally active chloride conductance, which is strongly modulated by cell volume and exhibits many properties identical to those of ICl.vol in native cells. A mutation of asparagine to lysine at position 579 at the end of the transmembrane domains of ClC-3 abolishes the outward rectification and changes the anion selectivity from I- > Cl- to Cl- > I- but leaves swelling activation intact. Because ClC-3 is a channel protein belonging to a large gene family of chloride channels, these results indicate that ClC-3 encodes ICl.vol in many native mammalian cells.

3T3 Cells↗
PubMed2002

Chloride channels and hepatocellular function: prospects for molecular identification.

Hepatocytes possess chloride channels at the plasma membrane and in multiple intracellular compartments. These channels are required for cell volume regulation and acidification of intracellular organelles. Evidence also supports a role of chloride channels in modulation of apoptosis and cell growth. Swelling- and Ca(2+)-activated chloride channels have been identified in hepatocyte plasma membranes, and chloride channels have been observed in the membranes of lysosomes, endosomes, Golgi, endoplasmic reticulum, mitochondria, and the nucleus. This review summarizes the functions of these channels and discusses the specific channel molecules they may represent. Chloride channel molecules shown to be expressed in hepatocytes include members of the ClC channel family (ClC-2, ClC-3, ClC-5, and ClC-7), members of the newly identified CLIC family of intracellular chloride channels (CLIC-1 and CLIC-4), the mitochondrial voltage-dependent anion channel, and a newly identified intracellular channel, MCLC (Mid-1 related chloride channel). Current understanding does not include a molecular identification of most of the observed channel functions, but details of the molecular properties of these channel molecules should allow future identification and further understanding of chloride channel function in hepatocytes.

Animals↗
PubMed2006

[Calcium-dependent chloride channels in plasma membrane of oocytes from toad, Bufo bufo gargarizans].

In this paper, membrane current properties of the fully-grown oocytes from toad, Bufo bufo gargarizans, were studied by using two-microelectrode voltage clamp technique. Axion of adult female toad was destroyed, and then ovarian lobes containing oocytes in stage I to VI were removed and incubated in Ca(2+)-free ND96 solution with collagenase (1.5 mg/ml) for 1 h. Subsequently, the oocytes were washed in Ca(2+)-free ND96 solution for 10 min to completely remove the follicular layer. For the experiments only the oocytes in stage V and VI were selected and used during 1 to 5 d. The membrane was depolarized from a holding potential of -80 mV to +60 mV in 10 mV step. It was found that a sustained outward current was elicited by depolarization. Potassium channel blockers (tetraethylammonium chloride, TEA, 10 mmol/L and 4-aminopyridine, 4-AP, 10 mmol/L) reduced the outward current to (23.4+/-0.72)% of the maximum. However, further addition of chloride channel blocker (5-nitro-2, 3-phenypropylamino benzoate, NPPB, 30 micromol/L) could almost completely block the outward current to (2.1+/-0.08)% of the maximum. In the presence of TEA and 4-AP, removal of extracellular Ca(2+) or adding verapamil (40 micromol/L), could also reduce the outward current to (2.2+/-0.04) % and (3.1+/-0.15) % of the maximum, respectively. It is concluded that calcium-dependent chloride channels exist in plasma membrane of Bufo bufo gargarizans oocytes, besides potassium channels.

4-Aminopyridine↗
PubMed2006

Regulation of the ClC-2 lung epithelial chloride channel by glycosylation of SP1.

Chloride channel-2 (ClC-2) is a pH- and voltage-activated chloride channel that is highly expressed in mammalian fetal airway epithelia during the period of maximal fluid secretion. A high level of luminal ClC-2 protein expression is maintained by the SP1 transcription factor until SP1 and ClC-2 decline rapidly at birth. Using fetal (preII-19) and adult (L2) rat lung Type 2 cell lines, we demonstrate that the active higher-molecular-weight 105-kD isoform of SP1 is phosphorylated and glycosylated. Exposure of either cell line to high-dose glutamine is sufficient to induce glycosylation of SP1 and to induce and maintain ClC-2. Exposure to tunicamycin to inhibit SP1 glycosylation reduces ClC-2 expression. We also demonstrate that in vivo ClC-2 expression is similarly regulated. SP1 from 6-wk-old murine lung (high ClC-2 expression) is hyperphosphorylated and hyperglycosylated compared with SP1 from 16-wk-old lung (low ClC-2 expression). Our results support the hypothesis that glycosylation of SP1 produces the 105-kD isoform of SP1 and is involved in regulating ClC-2 gene expression.

Animals↗
PubMed1991

[A flip-flop model of the chloride channel complex explains the dysregulation of the chloride flow in the plasmalemma of cells in cystic fibrosis].

The basic defect in cystic fibrosis is the chloride impermeability of the plasmalemma in different cells. A candidate for the chloride channel, thought to be affected in the syndrome, is "Porin 31HL" recently described by us. The molecule is i) expressed in the plasmalemma of different cells, it has ii) a molecular mass of 31,000 Daltons, it shows iii) high conductance in artificial membranes and it can be iv) modified by 4,4'-Diisothiocyanatostilbene-2,2'-disulfonate. A porin in the outer membrane of cells should furthermore v) be regulated by modulators. All these characters of "Porin 31HL" correspond to those given in literature for chloride channels. The regulation of the channels can be explained by a two component flip flop model.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗