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PubMed2001

ClC chloride channels.

SUMMARY: Chloride-conducting ion channels of the ClC family are emerging as critical contributors to a host of biological processes. These polytopic membrane proteins form aqueous pathways through which anions are selectively allowed to pass down their concentration gradients. The ClCs are found in nearly all organisms, with members in every mammalian tissue, yet relatively little is known about their mechanism or regulation. It is clear, however, that they are fundamentally different in molecular construction and mechanism from the well-known potassium-, sodium-, and calcium-selective channels. The medical importance of ClC channels - four inherited diseases have been blamed on familial ClC dysfunction to date - highlights their diverse physiological functions and provides strong motivation for further study.

Amino Acid Sequence↗
PubMed1995

Properties of voltage-gated chloride channels of the ClC gene family.

We review the properties of ClC chloride channels, members of an expanding gene family originally discovered by the cloning of the ClC-0 chloride channel from Torpedo electric organ. There are at least nine different ClC genes in mammals, several of which seem to be expressed ubiquitously, while others are expressed in a highly specific manner (e.g. the muscle-specific ClC-1 channel and the kidney-specific ClC-K channels). The newly cloned rat ClC-4 is strongly expressed in liver and brain, but also in heart, muscle, kidney and spleen. ClC chloride channels are structurally unrelated to other channel proteins and have twelve putative transmembrane domains. They function as multimers with probably four subunits. Functional characterization is most advanced with ClC-0, ClC-1 (mutations which cause myotonia) and ClC-2, a swelling-activated chloride channel. Many of the new ClC family members cannot yet be expressed functionally.

Amino Acid Sequence↗
PubMed2005

Intracellular chloride channels: critical mediators of cell viability and potential targets for cancer therapy.

The passage of ions to form and maintain electrochemical gradients is a key element for regulating cellular activities and is dependent on specific channel proteins or complexes. Certain ion channels have been the targets of pharmaceuticals that have had impact on a variety of cardiovascular and neurological diseases. Chloride channels regulate the movement of a major cellular anion, and in so doing they in part determine cell membrane potential, modify transepithelial transport, and maintain intracellular pH and cell volume. There are multiple families of chloride channel proteins, and respiratory, neuromuscular, and renal dysfunction may result from mutations in specific family members. Interest in chloride channels related to cancer first arose when the multidrug resistance protein (MDR/P-glycoprotein) was linked to volume-activated chloride channel activity in cancer cells from patients undergoing chemotherapy. More recently, CLC, CLIC, and CLCA intracellular chloride channels have been recognized for their contributions in modifying cell cycle, apoptosis, cell adhesion, and cell motility. Moreover, advances in structural biology and high-throughput screening provide a platform to identify chemical compounds that modulate the activities of intracellular chloride channels thereby influencing chloride ion transport and altering cell behavior. This review will focus on several chloride channel families that may contribute to the cancer phenotype and suggest how they may serve as novel targets for primary cancer therapy.

Amino Acid Sequence↗
PubMed1999

[The in vivo role of vascular chloride channels in the regulation of glomerular hemodynamics].

The calcium(Ca2+)-dependent chloride channel (CIC) may have a crucial role in the modulation of the effects of Angiotensin II (AII) on vascular smooth muscle cell and glomerular mesangium. We examined in vivo effects of a Ca(2+)-dependent chloride channel blocker, R(+)-methylindazone indanyloxy acetic acid 94 (IAA-94), on renal and glomerular hemodynamics in rats. A small needle was inserted from the kidney surface and the renal interstitium was directly perfused first with saline, control solution. For AII group, AII-concentrations were serially 10(-7) M, 10(-6) M, and 10(-5) M, and for AII and IAA-94 group, ratios of AII to IAA-94 (300 microM) the same serial concentrations. Perfusion with AII solution resulted in dose-dependent increase in renal vascular resistance (RVR), while no such elevation of RVR was observed under the perfusion with AII/IAA. To investigate the effects of Ca(2+)-dependent chloride channel on the regulatory mechanism of renal microcirculation, i.e., tubuloglomerular feed back (TGF) response, we performed micropuncture experiment. We measured proximal tubular stop-flow pressure (Psf) during the immersion of the corresponding nephron with drugs by the simultaneous perfusion of peritubular capillaries with the solutions containing AII (10(-7) M) or AII and IAA-94 (300 microM). TGF response was significantly enhanced by AII, while the increment in TGF response was completely abolished by concomitant IAA. Immersion with IAA-94 alone caused no alteration in TGF response. These data suggest that chloride channels could modulate AII action in renal and glomerular hemodynamics.

Angiotensin II↗
PubMed2003

Structure and pharmacology of swelling-sensitive chloride channels, I(Cl,swell).

Since several years, the interest for chloride channels and more particularly for the enigmatic swelling-activated chloride channel (I(Cl,swell)) is increasing. Despite its well-characterized electrophysiological properties, the I(Cl,swell) structure and pharmacology are not totally elucidated. These channels are involved in a variety of cell functions, such as cardiac rhythm, cell proliferation and differentiation, cell volume regulation and cell death through apoptosis. This review will consider different aspects regarding structure, electrophysiological properties, pharmacology, modulation and functions of these swelling-activated chloride channels.

Animals↗
PubMed2002

A biological role for prokaryotic ClC chloride channels.

An unexpected finding emerging from large-scale genome analyses is that prokaryotes express ion channels belonging to molecular families long studied in neurons. Bacteria and archaea are now known to carry genes for potassium channels of the voltage-gated, inward rectifier and calcium-activated classes, ClC-type chloride channels, an ionotropic glutamate receptor and a sodium channel. For two potassium channels and a chloride channel, these homologues have provided a means to direct structure determination. And yet the purposes of these ion channels in bacteria are unknown. Strong conservation of functionally important sequences from bacteria to vertebrates, and of structure itself, suggests that prokaryotes use ion channels in roles more adaptive than providing high-quality protein to structural biologists. Here we show that Escherichia coli uses chloride channels of the widespread ClC family in the extreme acid resistance response. We propose that the channels function as an electrical shunt for an outwardly directed virtual proton pump that is linked to amino acid decarboxylation.

Acids↗
PubMed2026

Transcriptomic and RNAi analyses reveal chloride channel 3-associated osmoregulation in Litopenaeus vannamei under low-salinity stress.

Chloride channels and transporters are important for cellular volume regulation and salinity adaptation in euryhaline crustaceans, yet the intestinal transcriptional relationship between plasma-membrane and intracellular chloride pathways remains unclear in Litopenaeus vannamei. In this study, RNA interference of anoctamin 1 (ANO1) was combined with intestinal transcriptome sequencing under the production-relevant low-salinity condition of salinity 3. ANO1 silencing produced a focused transcriptional response, with 16 differentially expressed genes (DEGs) identified (11 upregulated and 5 downregulated). Functional enrichment indicated that these genes were associated with transporter activity, cytoskeletal organization, extracellular matrix-receptor interaction, membrane lipid metabolism, and vesicular processes. Notably, a transcript encoding chloride channel protein 3 (CLC-3) was significantly upregulated following ANO1 knockdown, suggesting a potential transcriptional relationship between ANO1 and CLC-3 in chloride homeostasis. Based on this finding, CLC-3 was selected for full-length cDNA cloning, sequence characterization, salinity-gradient expression analysis, and RNAi-based functional assessment. The cloned CLC-3 cDNA was 2883 bp in length and encoded an 850 amino acid protein containing a conserved voltage-gated chloride channel (Voltage-CLC) domain and two cystathionine β-synthase domains. Phylogenetic analysis placed LvCLC-3 within the intracellular CLC-c clade, and tissue distribution analysis showed the highest CLC-3 expression in the intestine. Intestinal CLC-3 expression responded nonlinearly to salinity variation, peaking at salinity 20. Under salinity 3, CLC-3 knockdown reduced ANO1, Na+/K+-ATPase alpha subunit, and Na+-K+-2Cl- cotransporter transcript levels, whereas glutamate-gated chloride channel expression increased. Mild hepatopancreatic structural alterations were also observed after CLC-3 knockdown. These findings suggest that CLC-3 is a salinity-responsive intracellular chloride-transporter candidate associated with intestinal ion-transport-related transcriptional responses after ANO1 suppression in L. vannamei, although the underlying physiological mechanism requires further validation.

Animals↗
PubMed1987

Epithelial chloride channel. Development of inhibitory ligands.

Chloride channels are present in the majority of epithelial cells, where they mediate absorption or secretion of NaCl. Although the absorptive and secretory channels are well characterized in terms of their electrophysiological behavior, there is a lack of pharmacological ligands that can aid us in further functional and eventually molecular characterization. To obtain such ligands, we prepared membrane vesicles from bovine kidney cortex and apical membrane vesicles from trachea and found that they contain a chloride transport process that is electrically conductive. This conductance was reduced by preincubating the vesicles in media containing ATP or ATP-gamma-S, but not beta-methylene ATP, which suggests that the membranes contain a kinase that can close the channels. We then screened compounds derived from three classes: indanyloxyacetic acid (IAA), anthranilic acid (AA), and ethacrynic acid. We identified potent inhibitors from the IAA and the AA series. We tritiated IAA-94 and measured binding of this ligand to the kidney cortex membrane vesicles and found a high-affinity binding site whose dissociation constant (0.6 microM) was similar to the inhibition constant (1 microM). There was a good correlation between the inhibitory potency of several IAA derivatives and their efficacy in displacing [3H]IAA-94 from its binding site. Further, other chloride channel inhibitors, including AA derivatives, ethacrynic acid, bumetanide, and DIDS, also displaced the ligand from its binding site. A similar conductance was found in apical membrane vesicles from bovine trachea that was also inhibited by IAA-94 and AA-130B, but the inhibitory effects of these compounds were weaker than their effects on the renal cortex channel. The two drugs were also less potent in displacing [3H]IAA-94 from the tracheal binding site.

Animals↗
PubMed1991

Activation of gamma-aminobutyric acid insensitive chloride channels in mouse brain synaptic vesicles by avermectin B1a.

The interaction of avermectin B1a (AVMB1a) with mouse brain chloride channels was characterized using a radiochloride efflux assay. The loss of intravesicular chloride from synaptoneurosomes preloaded with 36Cl involved an initial rapid phase followed by a slower phase that approached equilibrium within 10 min. AVMB1a stimulated a 30% loss of intravesicular chloride within the first 2 s of exposure; however, AVMB1a had no effect on the rate of the slower phase of chloride loss. Experiments with lysed synaptoneurosomes showed that both chloride loading and basal and AVMB1a-stimulated chloride release required the presence of intact vesicles. The efflux of 36Cl from mouse brain synaptosomes and the stimulation of efflux by AVMB1a were qualitatively similar to the results obtained with synaptoneurosomes but involved much lower overall levels of chloride loading and release. AVMB1a produced half-maximal stimulation of chloride efflux from synaptoneurosomes at a concentration of 2.1 +/- 0.3 microM and a 35.4 +/- 1.4% maximal loss of intravesicular chloride at saturating concentrations. gamma-Aminobutyric acid (GABA), bicuculline, or the chloride channel blockers picrotoxinin, t-butylbicyclophosphorothionate (TBPS) 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), and anthracene 9-carboxylic acid (9-CA) had little or no effect on the loss of chloride from synaptoneurosomes either in the presence or the absence of AVMB1a. However, the chlorinated cycloalkane insecticides dieldrin and lindane were equally effective as inhibitors of GABA-dependent chloride uptake and AVMB1a-stimulated chloride efflux. These data demonstrate that AVMB1a-stimulated chloride efflux from mouse brain synaptic vesicles results from the activation of GABA-insensitive chloride channels and that this action is distinct from their previously documented effects on GABA-gated chloride channels in mouse brain preparations. Our findings imply that both GABA-gated and GABA-insensitive chloride channels may be toxicologically significant targets for the action of avermectins.

Animals↗
PubMed2004

Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin.

BACKGROUND & AIMS: Copper transport in hepatocytes is regulated by the interaction of multiple pumps, chaperones, and accessory proteins. Intracellular chloride channels are essential for copper metabolism in yeast but their role in Cu transport in hepatocytes is unknown. The aim of this study was to determine whether chloride channels are modulators of copper incorporation into ceruloplasmin (CP). METHODS: The effects of chloride concentration and chloride channel expression on secretion of holoCp and apoCp was measured by gel electrophoresis and immunoblotting. ClC family chloride channel expression in hepatocytes was determined by Western blotting. The association of ClC-4 and the Wilson's disease protein (ATP7B) was determined by co-immunoprecipitation. RESULTS: Chloride substitution reduced total Cp secretion and the ratio of secreted holoCp to apoCp (P = 0.038). The role of specific chloride channels was examined by cotransfection of ceruloplasmin and the chloride channel. Overexpression of ClC-4 doubled copper incorporation into ceruloplasmin (P = 0.011), whereas identical overexpression of ClC-3 had no effect. The effect of ClC-4 was most pronounced under copper-limiting conditions in which it increased copper incorporation more than 4-fold (P = 0.037). ClC-4 protein was abundant in hepatocyte membranes and was localized in intracellular vesicles containing ATP7B. CONCLUSIONS: ClC-4 is an intracellular chloride channel that stimulates copper incorporation into ceruloplasmin, probably by improving the efficiency of the ATP7B copper pump. It is thus an important component of the regulation of hepatic copper transport and may modulate Cu transport rates during copper deficiency, Wilson's disease, and other copper toxicosis syndromes.

Adenosine Triphosphatases↗
PubMed2002

The myotonia congenita mutation A331T confers a novel hyperpolarization-activated gate to the muscle chloride channel ClC-1.

Mutations in the muscle chloride channel gene CLCN1 cause myotonia congenita, an inherited disorder of skeletal muscle excitability leading to a delayed relaxation after muscle contraction. Here, we examine the functional consequences of a novel disease-causing mutation that predicts the substitution of alanine by threonine at position 331 (A331T) by whole-cell patch-clamp recording of recombinant mutant channels. A331T hClC-1 channels exhibit a novel slow gate that activates during membrane hyperpolarization and closes at positive potentials. This novel gate acts in series with fast opening and closing transitions that are common to wild-type (WT) and mutant channels. Under conditions at which this novel gate is not activated, i.e., a holding potential of 0 mV, the typical depolarization-induced activation gating of WT hClC-1 was only slightly affected by the mutation. In contrast, A331T hClC-1 channels with an open slow gate display an altered voltage dependence of open probability. These novel gating features of mutant channels produce a decreased open probability at -85 mV, the normal muscle resting potential, leading to a reduced resting chloride conductance of affected muscle fibers. The A331T mutation causes an unprecedented alteration of ClC-1 gating and reveals novel processes defining transitions between open and closed states in ClC chloride channels.

Adult↗
PubMedDate not supplied

The intracellular potassium and chloride channels: properties, pharmacology and function (review).

Channels selective for potassium or chloride ions are present in membranes of intracellular organelles such as sarcoplasmic (endoplasmic) reticulum, mitochondria, nucleus, synaptic vesicles, and chromaffin, and zymogen granules. They probably play an important role in cellular events such as compensation of electrical charges during transport of Ca2+, delta pH formation in mitochondria or V-ATPase containing membrane granules, and regulation of volume changes, due to potassium and chloride transport into intracellular organelles. Intracellular potassium and chloride channels could also be the target for pharmacologically active compounds. This mini-review describes the basic properties, pharmacology, and current hypotheses concerning the functional role of intracellular potassium and chloride channels.

Animals↗
PubMed2000

Mitochondrial potassium and chloride channels.

Channels selective for potassium or chloride ions are present in inner mitochondrial membranes. They probably play an important role in mitochondrial events such as the formation of delta pH and regulation of mitochondrial volume changes. Mitochondrial potassium and chloride channels could also be the targets for pharmacologically active compounds such as potassium channel openers and antidiabetic sulfonylureas. This review describes the properties, pharmacology, and current observations concerning the functional role of mitochondrial potassium and chloride channels.

Adenosine Triphosphate↗
PubMed2005

Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels.

ClC proteins are a family of chloride channels and transporters that are found in a wide variety of prokaryotic and eukaryotic cell types. The mammalian voltage-gated chloride channel ClC-1 is important for controlling the electrical excitability of skeletal muscle. Reduced excitability of muscle cells during metabolic stress can protect cells from metabolic exhaustion and is thought to be a major factor in fatigue. Here we identify a novel mechanism linking excitability to metabolic state by showing that ClC-1 channels are modulated by ATP. The high concentration of ATP in resting muscle effectively inhibits ClC-1 activity by shifting the voltage gating to more positive potentials. ADP and AMP had similar effects to ATP, but IMP had no effect, indicating that the inhibition of ClC-1 would only be relieved under anaerobic conditions such as intense muscle activity or ischemia, when depleted ATP accumulates as IMP. The resulting increase in ClC-1 activity under these conditions would reduce muscle excitability, thus contributing to fatigue. We show further that the modulation by ATP is mediated by cystathionine beta-synthase-related domains in the cytoplasmic C terminus of ClC-1. This defines a function for these domains as gating-modulatory domains sensitive to intracellular ligands, such as nucleotides, a function that is likely to be conserved in other ClC proteins.

Adenosine Diphosphate↗
PubMed2002

High-conductance chloride channels generate pacemaker currents in interstitial cells of Cajal.

BACKGROUND & AIMS: Interstitial cells of Cajal (ICCs) are responsible for slow, wave-driven, rhythmic, peristaltic motor patterns in the gastrointestinal tract. The aim was to identify and characterize the ion channels that generate the underlying pacemaker activity. METHODS: Single ion channel recordings were obtained from nonenzymatically isolated ICCs and studied by using the cell attached and inside-out configurations of the patch clamp technique. RESULTS: A high-conductance chloride channel was observed in ICCs that was spontaneously and rhythmically active at the same frequency as the rhythmic inward currents defining ICC pacemaker activity, 20-30 cycles/min at room temperature. Main conductance levels occurred between 122-144 pS and between 185-216 pS. Periodicity in the channel opening coincided with periodicity in membrane potential change, hence, at the single channel level, chloride channels were seen to be associated with the generation of rhythmic changes in membrane potential. CONCLUSIONS: ICCs harbor high-conductance chloride channels that participate in the generation of pacemaker activity and may become a target for pharmacologic treatment of gut motor disorders.

Animals↗
PubMed1996

Effect of chloride channel blockers on the cardiac CFTR chloride and L-type calcium currents.

OBJECTIVES: The aim of this study was to determine the effects of Cl- channel blockers on the cardiac cystic fibrosis transmembrane conductance regulator (CFTR) Cl- current (ICl) and the protein kinase A-regulated L-type calcium current (PKA-ICa). METHODS: Whole-cell ICl and ICa were recorded from isolated guinea pig ventricular myocytes using the patch clamp technique during stimulation of PKA by forskolin (1 or 2 microM). RESULTS: The inhibitory effects of clofibric acid, p-chlorophenoxy propionic acid, gemfibrozil, diphenylamine-2-carboxylate (DPC), anthracene-9-carboxylate, 4,4'dinitrostilbene-2,2'-disulfonic acid and indanyloxyacetic acid 94 were examined on the two currents. Clofibric acid (1 mM), p-chlorophenoxy propionic acid (1 mM) and gemfibrozil (250 microM) produced an approximate 50% decrease in ICl, but had no effect on the PKA-ICa. Surprisingly, application of DPC (500 microM and 1 mM) and anthracene-9-carboxylate (500 microM) strongly reduced both currents. However, inhibition of the Ca2+ and Cl- channels by DPC could be differentiated in two important ways. First, increasing the pH of the external solution from 7.4 to 10.0 prevented the block of ICl by DPC, but did not attenuate the reduction in the PKA-ICa. Second, DPC inhibited the PKA-ICa in mouse atrial myocytes which lacked ICl. Neither 4,4'dinitrostilbene-2,2'-disulfonic acid (100 microM) nor indanyloxyacetic acid 94 (50 microM) caused any change in either of the guinea pig ventricular currents. CONCLUSIONS: Drugs such as DPC and anthracene-9-carboxylate which block the cardiac CFTR Cl- channel also inhibit the regulation of the L-type ICa. During beta-adrenergic stimulation, changes produced by these drugs on the cardiac action potential duration will be attributable to inhibition of both the Cl- and Ca2+ currents. Analogues of clofibric acid may serve as selective blockers of the CFTR Cl- channel that can be used to determine the physiological function of ICl in cardiac excitation.

Animals↗
PubMed1997

A patch clamp study of a glutamatergic chloride channel on pharyngeal muscle of the nematode Ascaris suum.

Glutamatergic chloride channels on the pharyngeal muscle of Ascaris suum could be activated with glutamate and ivermectin and reversibly blocked with picrotoxin using the patch clamp technique. No activation was observed with GABA, glycine and acetylcholine. Most of the current was carried by the main subconductance state of 21 pS. Two smaller subconductance states occurred rarely. Open time histograms could be best fitted by two time constants of tau(o1) = 0.33 ms and tau(o2) = 9.8 ms present at all glutamate concentrations applied. The results suggest that some properties of the channel investigated here are different from other glutamatergic chloride channels reported from various animals.

Acetylcholine↗
PubMed2005

Differential expression of the human chloride channel genes in the trabecular meshwork under stress conditions.

Among other channels, voltage-gated chloride channels (ClC) regulate cell volume, membrane potential and cellular transport. Because changes in trabecular meshwork (TM) cell volume influence outflow facility and because the relative abundance of a gene's transcript is an indication of the relevance of the gene's function, we investigated the presence and relative expression of seven members of the CLCN gene family in the human TM. To elucidate the role of ClC-2 and ClC-3 in cell swelling, we studied changes in their mRNA levels after hypotonic shock. In addition, to examine the potential involvement of these two channels in conditions associated with glaucoma, we determined their transcripts levels in response to elevated intraocular pressure (IOP) and dexamethasone (DEX). For our evaluations, we used non-transformed human TM cells and perfused human anterior segments from post-mortem donors. For hypotonic shock, cells were exposed to 260 mOsm kg(-1) medium for 15 and 30 min. For DEX, cells were treated with 0.1 microm DEX for 1, 4 and 10 days. For elevated IOP, one eye of each pair of perfused human anterior segments was subjected to DeltaP 38+/-4 mm Hg for 1 hr, 4 and 7 days while the contralateral remained at baseline pressure as a control. ClCs transcripts were determined by relative quantitative RT-PCR. Our results showed that all transcripts but ClC-1 were detected in HTM cells. ClC-2 and ClC-3 were the most abundant and comprised about twice the amount of ClC-6 and ClC-7 and four times that of ClC-4 and ClC-5. Hypotonic conditions consistently up regulated CLCN2 and slightly up regulated CLCN3. After short periods of elevated pressure, ClC-2 and ClC-3 transcripts were increased but ClC-2 induction was significantly higher than that of ClC-3. In contrast, after long pressure insults (7 days), ClC-3 mRNA was significantly increased while CLCN2 was not changed. DEX treatment markedly down regulated CLCN3 and little, if any, reduced ClC-2. The extent of response of the CLCN2 and CLCN3 to these conditions was markedly affected by individual traits but at all times maintained the relative expression pattern of both genes. CLCN2 gene expression was predominantly influenced by cell volume regulation while that of CLCN3 was preferentially affected by conditions associated with TM pathology.

CLC-2 Chloride Channels↗