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PubMed2000

Glycine-gated chloride channels in neutrophils attenuate calcium influx and superoxide production.

Recently, it was demonstrated that liver injury and TNF-alpha production as a result of endotoxin (lipopolysaccharide, LPS) were attenuated by feeding animals a diet enriched with glycine. This phenomenon was shown to be a result of, at least in part, activation of a chloride channel in Kupffer cells by glycine, which hyperpolarizes the cell membrane and blunts increases in intracellular calcium concentrations ([Ca(2+)](i)) similar to its action in the neuron. It is well known that hepatotoxicity due to LPS has a neutrophil-mediated component and that activation of neutrophils is dependent on increases in [Ca(2+)](i). Therefore, the purpose of this study was to determine if glycine affected agonist-induced increases in [Ca(2+)](i) in rat neutrophils. The effect of glycine on increases in [Ca(2+)](i) elicited either by the bacterial-derived peptide formyl-methionine-leucine-phenylalanine (FMLP) or LPS was studied in individual neutrophils using Fura-2 and fluorescence microscopy. Both FMLP and LPS caused dose-dependent increases in [Ca(2+)](i), which were maximal at 1 microM FMLP and 100 microgram/ml LPS, respectively. LPS increased intracellular calcium in the presence and absence of extracellular calcium. Glycine blunted increases in [Ca(2+)](i) in a dose-dependent manner with an IC(50) of approximately 0.3 mM, values only slightly higher than plasma levels. Glycine was unable to prevent agonist-induced increases in [Ca(2+)](i) in chloride-free buffer. Moreover, strychnine (1 microM), an antagonist of the glycine-gated chloride channel in the central nervous system, reversed the effects of glycine (1 mM) on FMLP- or LPS-stimulated increases in [Ca(2+)](i). To provide hard evidence for a glycine-gated chloride channel in the neutrophil, the effect of glycine on radioactive chloride uptake was determined. Glycine caused a dose-dependent increase in chloride uptake into neutrophils with an ED(50) of approximately 0.4 mM, an effect also prevented by 1 microM strychnine. Glycine also significantly reduced the production of superoxide anion from FMLP-stimulated neutrophils. Taken together, these data provide clear evidence that neutrophils contain a glycine-gated chloride channel that can attenuate increases in [Ca(2+)](i) and diminish oxidant production by this important leukocyte.

Animals↗
PubMed2002

Selective elimination of glutamate activation and introduction of fluorescent proteins into a Caenorhabditis elegans chloride channel.

Glutamate-gated chloride (GluCl) channels from invertebrates can be activated by ivermectin (IVM) to produce electrical silencing in mammalian neurons. To improve this GluCl/IVM strategy, we sought to mutate the Caenorhabditis elegans GluCl channels so that they become insensitive to glutamate but retain their sensitivity to IVM. Based on structure-function studies of nicotinic acetylcholine receptor superfamily members, we tested in oocytes 19 point mutants at 16 residues in the beta-subunit likely to be involved in the response to glutamate. Y182F reduces the glutamate response by greater than six-fold, with little change to IVM responses, when coexpressed with wild-type (WT) GluCl alpha. For GluCl alphabeta(Y182F), the EC(50) and Hill coefficient for glutamate are similar to those of WT, indicating that the mutant decreases the efficacy of glutamate, but not the potency. Also, fluorescent proteins (enhanced green fluorescent protein, enhanced yellow fluorescent protein, enhanced cyan fluorescent protein; XFP) were inserted into the M3-M4 loop of the GluCl alpha, beta and beta(Y182F). We found no significant functional difference between these XFP-tagged receptors and WT receptors. The modified GluCl channel, without glutamate sensitivity but with a fluorescent tag, may be more useful in GluCl silencing strategies.

Amino Acid Sequence↗
PubMed2004

Development of a colorimetric method for functional chloride channel assay.

Anion channels play significant physiological roles in humans and animals. However, the effort of screening for anion channel modulators was limited by the available assay technologies. This report discusses the development of a cell-based functional chloride channel assay using iodine as the chloride channel functional indicator. Iodine concentrations were measured with modified Sandell-Kolthoff reaction using colorimetric detection. The assay was rapid and quantitative. When WSS-1 cells were activated by gamma-aminobutyric acid (GABA) in the condition that gamma-aminobutyric acid type A receptor (GABAA receptor) conducted outwardly rectifying chloride channel function, the EC50 of GABA was 7.69 microM. IC50s were 0.53 microM for bicuculline and 3.1 microM for picrotoxin, respectively, in the presence of 10 microM GABA. When Capan-1 cells were activated by forskolin, the EC50 was 0.14 microM. The assay can also be applied to inwardly rectifying anion channels as exemplified by GABAA channel with an EC50 of 294 microM. Thus, the assay is universal and reliable and can be used for anion channel high-throughput screening.

Biological Assay↗
PubMed2001

ClC-5 chloride channel and kidney stones: what is the link?

Nephrolithiasis is one of the most common diseases in the Western world. The disease manifests itself with intensive pain, sporadic infections, and, sometimes, renal failure. The symptoms are due to the appearance of urinary stones (calculi) which are formed mainly by calcium salts. These calcium salts precipitate in the renal papillae and/or within the collecting ducts. Inherited forms of nephrolithiasis related to chromosome X (X-linked hypercalciuric nephrolithiasis or XLN) have been recently described. Hypercalciuria, nephrocalcinosis, and male predominance are the major characteristics of these diseases. The gene responsible for the XLN forms of kidney stones was cloned and characterized as a chloride channel called ClC-5. The ClC-5 chloride channel belongs to a superfamily of voltage-gated chloride channels, whose physiological roles are not completely understood. The objective of the present review is to identify recent advances in the molecular pathology of nephrolithiasis, with emphasis on XLN. We also try to establish a link between a chloride channel like ClC-5, hypercalciuria, failure in urine acidification and protein endocytosis, which could explain the symptoms exhibited by XLN patients.

Animals↗
PubMed1995

ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family.

We cloned two novel members of the CLC chloride channel family from rat and human brain. ClC-6 is a 97-kDa protein, and ClC-7 a 89-kDa protein roughly 45% identical with ClC-6. Together they define a new branch of this gene family. Both genes are very broadly expressed, e.g. in brain, testes, muscle and kidney. In mouse embryos, both genes are expressed as early as day 7. While the human gene for ClC-6 is located on human chromosome 1p36 and shares this region with hClC-Ka and hClC-Kb, ClC-7 is on 16p13. ClC-6 has a highly conserved glycosylation site between transmembrane domains D8 and D9, while ClC-7 is the only known eukaryotic ClC protein which lacks this site. Hydropathy analysis indicates that domain D4 cannot serve as a transmembrane domain. Both ClC-6 and ClC-7 cannot be expressed as chloride channels in Xenopus oocytes, either singly or in combination.

Amino Acid Sequence↗
PubMed2000

A decade of CLC chloride channels: structure, mechanism, and many unsettled questions.

ClC-type chloride channels are ubiquitous throughout the biological world. Expressed in nearly every cell type, these proteins have a host of biological functions. With nine distinct homologues known in eukaryotes, the ClCs represent the only molecularly defined family of chloride channels. ClC channels exhibit features of molecular architecture and gating mechanisms unprecedented in other types of ion channels. They form two-pore homodimers, and their voltage-dependence arises not from charged residues in the protein, but rather via coupling of gating to the movement of chloride ions within the pore. Because the functional characteristics of only a few ClC channels have been studied in detail, we are still learning which properties are general to the whole family. New approaches, including structural analyses, will be crucial to an understanding of ClC architecture and function.

Animals↗
PubMed1995

Absence of the skeletal muscle sarcolemma chloride channel ClC-1 in myotonic mice.

The voltage-dependent chloride channel ClC-1 stabilizes resting membrane potential in skeletal muscle. Mutations in the ClC-1 gene are responsible for both human autosomal recessive generalized myotonia and autosomal dominant myotonia congenita. To understand the tissue distribution and subcellular localization of ClC-1 and to evaluate its role in an animal model of myotonia, antibodies were raised against the carboxyl terminus of this protein. Expression of the 130-kDa ClC-1 protein is unique to skeletal muscle, consistent with its mRNA tissue distribution. Immunolocalization shows prominent ClC-1 antigen in the sarcolemma of both type I and II muscle fibers. Sarcolemma localization is confirmed by Western analysis of skeletal muscle subcellular fractions. The ADR myotonic mouse (phenotype ADR, genotype adr/adr), in which defective ClC-1 mRNA has been identified, is shown here to be absent in ClC-1 protein expression, whereas other skeletal muscle sarcolemma protein expression appears normal. Immunohistochemistry of skeletal muscle from ADR and other mouse models of human muscle disease demonstrate that the absence of ClC-1 chloride channel is a defect specific to ADR mice.

Amino Acid Sequence↗
PubMed1994

Cloning and expression of a protein kinase C-regulated chloride channel abundantly expressed in rat brain neuronal cells.

cDNA (CIC-3) encoding a protein kinase C-regulated chloride channel was cloned and characterized. The open reading frame encodes 760 amino acids, which possess significantly amino acid identity with previously cloned CIC chloride channels. The chloride currents expressed in Xenopus oocytes injected with CIC-3 cRNA were completely blocked by activation of protein kinase C by 12-O-tetradecanoylphorbol 13-acetate. Abundant expression of CIC-3 mRNA was observed in rat brain, especially in the olfactory bulb, hippocampus, and cerebellum. These findings suggest that CIC-3 may play an important role in neuronal cell function through regulation of membrane excitability by protein kinase C.

Amino Acid Sequence↗
PubMed1991

Studies on the ionic selectivity of the GABA-operated chloride channel on the somatic muscle bag cells of the parasitic nematode Ascaris suum.

The reversal potential for the GABA-elicited hyperpolarization (EGABA) of the muscle bag cells of the parasite nematode Ascaris suum is near to the equilibrium potential for chloride ions (ECl) indicating that this is a chloride-mediated event. The value of EGABA in the presence of different anions indicates the selectivity sequence of the GABA-operated chloride channel as SCN- greater than Br-, I- greater than ClO3-, NO3-, Cl- greater than C2H5COO- greater than CH3COO-, HCOO-, OHCH2CH2SO3H-, CH3SO4-, BrO3-, SO4(2-). The cut-off point in terms of relative hydrated size for permeation is between ClO3- and BrO3- suggesting that the diameter of the channel is between 0.29 and 0.33 nm. The selectivity sequence of the resting membrane chloride channels was indicated by the degree of muscle cell hyperpolarization upon addition of the anion to the bathing medium and was SCN- greater than NO3- greater than I-, Br-, greater than ClO3- greater than Cl-. These sequences are consistent with the anions interacting with a cationic site of low field strength at the selectivity determining portion of the channel for both the GABA-operated and the resting chloride channel.

Animals↗
PubMed2005

Calcium and chloride channel activation by angiotensin II-AT1 receptors in preglomerular vascular smooth muscle cells.

The pathways responsible for the rapid and sustained increases in [Ca(2+)](i) following activation of ANG II receptors (AT(1)) in renal vascular smooth muscle cells were evaluated using fluorescence microscopy. Resting intracellular calcium concentration [Ca(2+)](i) averaged 75 +/- 9 nM. The response to ANG II (100 nM) was characterized by a rapid initial increase of [Ca(2+)](i) by 74 +/- 6 nM (n = 35) followed by a decrease to a sustained level of 12 +/- 2 nM above baseline. The average time from peak to 50% reduction from the peak value (50% time point) was 32 +/- 4 s. AT(1) receptor blockade with 1 microM candesartan (n = 5) prevented the responses to ANG II. In nominally calcium-free conditions (n = 8), the peak increase in [Ca(2+)](i) averaged 42 +/- 7 nM but the sustained phase was absent and the 50% time point was reduced to 11 +/- 4 s. L-type calcium channel blockade with diltiazem reduced the peak [Ca(2+)](i) to 24 +/- 8 nM and the sustained level to 4 +/- 2 nM (n = 10). In cells preincubated in low Cl(-) (3.0 mM), the peak response to ANG II was suppressed as was the sustained response. Blockade of chloride channels with DIDS eliminated both the peak and sustained responses (n = 11); chloride channel blockade with DPC (n = 17) suppressed the peak increase in [Ca(2+)](i) to 18 +/- 5 and also prevented the sustained response. IP3 receptor blockade by 10 microM TMB-8 (n = 6) reduced the peak to 22 +/- 8 and prevented the sustained response. Exposure to 10 microM TMB-8 in the presence of Ca(2+)-free medium prevented the ANG II response (n = 9). In the presence of 100 microM DPC and 10 microM TMB-8 (n = 7), the ANG II response was also prevented. Thus the rapid initial increase in [Ca(2+)](i) is due not only to release from intracellular stores, but also to Ca(2+) influx from the extracellular fluid. Although Ca(2+) entry via L-type calcium channels is responsible for the major portion of the sustained response, other entry pathways participate. The finding that chloride channel blockers markedly attenuate both rapid and sustained responses indicates that chloride channel activation contributes to, rather than being the consequence of, the initial rapid response.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2003

Evidence for a functional interaction between the ClC-2 chloride channel and the retrograde motor dynein complex.

The ClC-2 chloride channel has been implicated in essential physiological functions. Analyses of ClC-2 knock-out mice suggest that ClC-2 expression in retinal pigment epithelia and Sertoli cells normally supports the viability of photoreceptor cells and male germ cells, respectively. Further, other studies suggest that ClC-2 expression in neurons may modify inhibitory synaptic transmission via the gamma-aminobutyric acid, type A receptor. However, complete understanding of the physiological functions of ClC-2 requires elucidation of the molecular basis for its regulation. Using cell imaging and biochemical and electrophysiological techniques, we show that expression of ClC-2 at the cell surface may be regulated via an interaction with the dynein motor complex. Mass spectrometry and Western blot analysis of eluate from a ClC-2 affinity matrix showed that heavy and intermediate chains of dynein bind ClC-2 in vitro. The dynein intermediate chain co-immunoprecipitates with ClC-2 from hippocampal membranes suggesting that they also interact in vivo. Disruption of dynein motor function perturbs ClC-2 localization and increases the functional expression of ClC-2 in the plasma membranes of COS7 cells. Thus, cell surface expression of ClC-2 may be regulated by dynein motor activity. This work is the first to demonstrate an in vivo interaction between an ion channel and the dynein motor complex.

Animals↗
PubMed1989

A cAMP-regulated chloride channel in lymphocytes that is affected in cystic fibrosis.

A defect in regulation of a chloride channel appears to be the molecular basis for cystic fibrosis (CF), a common lethal genetic disease. It is shown here that a chloride channel with kinetic and regulatory properties similar to those described for secretory epithelial cells is present in both T and B lymphocyte cell lines. The regulation of the channels by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase in transformed B cells from CF patients is defective. Thus, lymphocytes may be an accessible source of CF tissue for study of this defect, for cloning of the chloride channel complex, and for diagnosis of the disease.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Pharmacology of CFTR chloride channel activity.

Pharmacology of CFTR Chloride Channel Activity. Physiol. Rev. 79, Suppl.: S109-S144, 1999. - The pharmacology of cystic fibrosis transmembrane conductance regulator (CFTR) is at an early stage of development. Here we attempt to review the status of those compounds that modulate the Cl- channel activity of CFTR. Three classes of compounds, the sulfonylureas, the disulfonic stilbenes, and the arylaminobenzoates, have been shown to directly interact with CFTR to cause channel blockade. Kinetic analysis has revealed the sulfonylureas and arylaminobenzoates interact with the open state of CFTR to cause blockade. Suggestive evidence indicates the disulfonic stilbenes act by a similar mechanism but only from the intracellular side of CFTR. Site-directed mutagenesis studies indicate the involvement of specific amino acid residues in the proposed transmembrane segment 6 for disulfonic stilbene blockade and segments 6 and 12 for arylaminobenzoate blockade. Unfortunately, these compounds (sulfonylureas, disulfonic stilbenes, arylaminobenzoate) also act at a number of other cellular sites that can indirectly alter the activity of CFTR or the transepithelial secretion of Cl-. The nonspecificity of these compounds has complicated the interpretation of results from cellular-based experiments. Compounds that increase the activity of CFTR include the alkylxanthines, phosphodiesterase inhibitors, phosphatase inhibitors, isoflavones and flavones, benzimidazolones, and psoralens. Channel activation can arise from the stimulation of the cAMP signal transduction cascade, the inhibition of inactivating enzymes (phosphodiesterases, phosphatases), as well as the direct binding to CFTR. However, in contrast to the compounds that block CFTR, a detailed understanding of how the above compounds increase the activity of CFTR has not yet emerged.

Animals↗
PubMed1996

Phosphorylation-dependent block of cystic fibrosis transmembrane conductance regulator chloride channel by exogenous R domain protein.

The cystic fibrosis transmembrane conductance regulator (CFTR) constitutes a linear conductance chloride channel, which is regulated by cAMP-dependent protein kinase phosphorylation at multiple sites located in the intracellular regulatory (R) domain. Studies in a lipid bilayer system, reported here, provide evidence for the control of CFTR chloride channel by its R domain. The exogenous R domain protein (encoded by exon 13 plus 85 base pairs of exon 14) interacted specifically with the CFTR molecule and inhibited the chloride conductance in a phosphorylation-dependent manner. Only the unphosphorylated R domain protein blocked the CFTR channel. Such functional interaction suggests that the putative gating particle of the CFTR chloride channel resides in the R domain.

Base Sequence↗
PubMed2005

[Reversal effect of haloperidol on doxorubicin resistance and chloride channel inhibition in erythroleukemic cell K562/Dox].

OBJECTIVE: To investigate the reversal effect of haloperidol (Hal) on doxorubicin (Dox) resistance and its inhibition effect on P-glycoprotein and swelling-activated chloride channel in Dox-resistant erythro-leukemic cell line K562/Dox. METHODS: Tumor cell proliferation was measured by LDH assay. mRNA expressions of P-glycoprotein (MDR1), glutathione S-transferase Pi (GSTpi) and MDR-associated protein (MRP) of K562/Dox treated with Hal were assayed by RT-PCR. Chloride-sensitive dye MQAE was loaded into K562/Dox cells and the intracellular fluorescence intensity was measured to evaluate the effect of Hal on chloride channel in swelling-activated K562/Dox cells. Coulter counter ZM and Channelyzer 256 were used to measure cell volume regulation. RESULTS: Hal significantly reversed Dox resistance in K562/Dox cells after 12.50, 6.25 and 3.12 micromol/L Hal treatment, the chemosensitivity to Dox increased by 8.61, 4.35 and 2.25 times respectively. After treatment with Hal 12.50 micromol/L, MDR1 and MRP mRNA expression were gradually down-regulated in a time-dependent manner on d1-d3, reducing to 76.3% and 64.6% of the control level on d3 (P < 0.05), while GSTpi mRNA expression decreased by 66.1% (P < 0.05) on d1-d2, and began to recover on d3. The swelling-activated chloride channel and cell regulatory volume decreased (RVD) in K562/Dox cells were also inhibited by Hal. Under hypotonic challenge the cellular fluorescence intensity which represented chloride concentration declined by (34.46 +/- 5.91)%. After adding 6.25 micromol/L and 18.75 micromol/L Hal, the hypotonic challenge only caused decrease in fluorescence intensity by (24.43 +/- 3.25)% and (16.63 +/- 4.98)% (P < 0.01). RVD in hypotonic condition was (84.95 +/- 5.69)%. RVD under hypotonic condition with 6.25 micromol/L and 18.75 micromol/L Hal were (51.12 +/- 6.01)% and (39.51 +/- 4.79)% respectively (P < 0.01). CONCLUSION: A nontoxic concentration of haloperidol can significantly reverse drug resistance through a multi-pathway effect, including down-regulating mRNA expressions of MDR, GSTpi and MRP, inhibition of swelling-activated chloride channel and RVD in K562/Dox cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Influence of muscle activity on the actions of chloride channel blockers in the mouse skeletal muscle.

The purpose of this work was to investigate the effect of channel blockers in the presence and absence of nerve and/or muscle activity. 9-Anthracenecarboxylic acid (0.03 mM), a chloride channel blocker, increased both the amplitude and duration of the contractile response to direct stimulation in the mouse soleus muscle in either low Ca2+ Krebs (0.25 mM) or normal Ca2+ Krebs (2.5 mM) containing 0.1 mM 4-aminopyridine (potassium channel blocker). In addition, spontaneous contractions were induced by 9-anthracenecarboxylic acid in low Ca2+ Krebs. On the other hand, the combination of two potassium channel blockers, 4-aminopyridine (0.3 mM) plus tetraethylammonium ion (10 mM), increased the twitch amplitude but only slightly increased the contractile duration in the mouse soleus muscle in normal Krebs. The contraction-potentiating actions of 9-anthracenecarboxylic acid were inhibited by denervation, while those of 4-aminopyridine plus tetraethylammonium were not. Chronic exposure to the sciatic nerve to a lidocaine-cuff, but not to a colchicine-cuff, exhibited similar effects as denervation. Direct electrical stimulations were applied for 2 days to the soleus muscle through implanted teflon-coated multistranded electrodes in vivo, beginning immediately after denervation or cuff treatments. The contraction-potentiating effects of 4-aminopyridine plus 9-anthracenecarboxylic acid or 9-anthracenecarboxylic acid in low Ca2+ Krebs were restored in the denervated or lidocaine-cuff-treated soleus muscle by chronic direct stimulations. The membrane potential and input resistance of muscle fibres and the effects of 9-anthracenecarboxylic acid, which were altered by denervation or cuff treatment, were also partially restored by this measure. When sciatic nerves had been treated with lidocaine-cuff for 4 days and the cuff was then removed for 7 days, the contraction-potentiating effects of 9-anthracenecarboxylic acid were also restored. Four days after Achilles tenotomy, the contraction-potentiating effects of 9-anthracenecarboxylic acid were markedly inhibited. It was concluded that muscle activity controls the properties of chloride channels and that neural activity may affect the properties of chloride channels via enhancement of the muscle contraction.

4-Aminopyridine↗
PubMed2004

Agonist enhacement of macrocyclic lactone activity at a glutamate-gated chloride channel subunit from Haemonchus contortus.

The mode of action of ivermectin (IVM) in nematodes appears to be the opening of inhibitory ion channels, including the glutamate-gated chloride channel (GluCl). Recently, it has been shown that IVM binds with high affinity to a Haemonchus contortus GluCl subunit (HcGluCla) expressed in COS-7 cells, and this binding is potentiated in the presence of glutamate. To gain further insight into the potentiation of macrocyclic lactone anthlemintics we have screened various glutamatergic and nonglutamatergic ligands for their ability to enhance [ 3H ] IVM binding to HcGluCla. Of the ligands tested, only glutamate and ibotenate potentiated [ 3H ] IVM binding. Interestingly, these ligands have also been shown to open the HcGluCla channel expressed in Xenopus oocytes. We examined the effect of ibotenate on macrocyclic lactone binding in more detail and found that it caused a 7-fold enhancement in [ 3H ] IVM binding affinity and a 4-fold increase in [ 3H ] MOX binding affinity. In in vivo efficacy studies, ibotenate (up to 2mg/kg) had no anthelmintic activity against H. contortus in gerbils. When 1mg/kg ibotenate was used in combination with IVM, IVM efficacy increased by 15% ( P=0.048 ). These results demonstrate that a GluCl agonist enhances IVM activity and provides further information on the mode of action of ivermectin in parasitic nematodes.

Animals↗
PubMed1993

Significance of chloride channel activation in the gamma-aminobutyric acid induced growth hormone secretion in the neonatal rat pituitary.

Growth hormone (GH) secretion of the neonatal pituitary is stimulated by tau-aminobutyric acid (GABA) (1,2). Since in most cases GABA is known to act by increasing postsynaptic membrane permeability to chloride ions we tested the importance of chloride channel activation in the GH stimulatory effect of GABA in the neonatal pituitary. In the absence of chloride in the superfusion medium GABA was without effect on GH secretion of the neonatal pituitaries and its effect was attenuated by chloride channel inhibitors. The effect of growth hormone releasing hormone (GHRH) on GH secretion was attenuated in the chloride-free media, but it was not affected by simultaneous administration of chloride channel blockers. The present study indicates that GH stimulatory effect of GABA in the neonatal pituitaries might involve chloride channel activation probably resulting in secondary activation of calcium channels.

Animals↗