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PubMed1995

Chloride channels and cystic fibrosis of the pancreas.

Cystic fibrosis (CF) affects approximately 1 in 2000 people making it one of the commonest fatal, inherited diseases in the Caucasian population. CF is caused by mutations in a cyclic AMP-regulated chloride channel known as CFTR, which is found on the apical plasma membrane of many exocrine epithelial cells. In the CF pancreas, dysfunction of the CFTR reduces the secretory activity of the tubular duct cells, which leads to blockage of the ductal system and eventual fibrosis of the whole gland. One possible approach to treating the disease would be to activate an alternative chloride channel capable of bypassing defective CFTR. A strong candidate for this is a chloride channel regulated by intracellular calcium, which has recently been shown to protect the pancreas in transgenic CF mice. Pharmacological intervention directed at activating this calcium-activated Cl- conductance might provide a possible therapy to treat the problems of pancreatic dysfunction in CF.

Animals↗

PubMed1998

Calcium release and calcium-activated chloride channels in airway smooth muscle cells.

Rapid progress has been made in the determination of specific ion channels expressed in airway smooth muscle cells and their role in excitation-contraction coupling. The combination of molecular biology and molecular physiology has provided insight into the properties of voltage-dependent cation (calcium and potassium) channels and their regulation by excitatory and inhibitory signaling processes. In this brief review, we will focus on calcium release and calcium-activated chloride channels. The former channels mediate receptor-activated calcium release, and the latter channels are opened following this release event. Moreover, the discovery of spontaneous calcium release events, or "calcium sparks," in smooth muscle, suggests an unanticipated level of regulation. Intracellular calcium release can drive electrical activity by the activation of calcium-dependent sarcolemmal ion channels, including calcium-activated chloride channels. These channels activate briefly but undergo a rapid phosphorylation by calcium/calmodulin-dependent protein kinase, which uncouples channel activity from cytosolic calcium. The coupling between intracellular calcium release and depolarizing chloride currents represents a potentially important signaling system in airway smooth muscle.

Bronchi↗

PubMed1992

Reconstitution and regulation of an epithelial chloride channel.

We have used a monoclonal antibody (MAb E12), one of several such antibodies raised against theophylline-treated Necturus gallbladder epithelial cells, to isolate a chloride channel protein by the use of an immunoaffinity column and FPLC. This protein (M(r) 219,000) has been reconstituted into a planar lipid bilayer, where it behaves as a chloride-selective channel (PCl/PNa = 20.2; PNa/PK = 1) whose unit conductance is 62.4 +/- 4.6 pS. Antibody added to the trans side (there is no effect from the cis side) causes channel open probability to drop to virtually zero, but has no effect on the conductance or the selectivity of single channels. To test the role of phosphorylation in the activity of the native channel, we studied the effects of the protein phosphatase inhibitor okadaic acid (OA) on intact gallbladders, and showed that channels opened by theophylline treatment and closed by antibody are reopened reversibly by OA (0.01-1.0 microM). Addition of the catalytic subunit of protein phosphatase 2A (PP-2A) to the cis side of a bilayer containing reconstituted chloride channels caused closure of the channels after a delay, and subsequent addition of ATP and the catalytic subunit of cAMP-dependent protein kinase (PKA) caused immediate reopening. These data indicate that (a) this chloride channel protein inserts in a directed way into the bilayer such that the cis side is 'intracellular', (b) the purified channel protein is phosphorylated, and (c) gating from the cellular side is controlled by the direct phosphorylation and dephosphorylation of the channel protein.

Animals↗

PubMed1992

Intrinsic lethality of chloride-channel-directed insecticides and convulsants in mammals.

The intrinsic lethality of a series of chloride-channel-directed convulsants and insecticides was determined by intracerebral injection into mice. The toxicities of the cyclodiene insecticides and picrotoxinin were potentiated by intracerebral injection, when compared to their reported intraperitoneal LD50s. In contrast, the toxicities of lindane, abamectin, and the bicyclic convulsants TBPS and a TBOB analog were approximately the same by either route of administration. These results suggest that the brain is the primary target site for the cyclodienes and picrotoxinin, while the peripheral nervous system may be relatively more important in the toxic action of lindane, abamectin, and bicyclic convulsants such as TBPS. With the exception of picrotoxinin these compounds showed, overall, a good correlation between acute intracerebral toxicity and potency for inhibiting GABA-dependent chloride uptake. The evidence that multiple chloride-channel subtypes serve as targets for these compounds and the potential impact this had on the results of these studies are discussed.

Animals↗

PubMed2002

Ivermectin and nodulisporic acid receptors in Drosophila melanogaster contain both gamma-aminobutyric acid-gated Rdl and glutamate-gated GluCl alpha chloride channel subunits.

35S-labeled derivatives of the insecticides nodulisporic acid and ivermectin were synthesized and demonstrated to bind with high affinity to a population of receptors in Drosophila head membranes that were previously shown to be associated with a glutamate-gated chloride channel. Nodulisporic acid binding was modeled as binding to a single population of receptors. Ivermectin binding was composed of at least two kinetically distinct receptor populations, only one of which was associated with nodulisporic acid binding. The binding of these two ligands was modulated by glutamate, ivermectin, and antagonists of invertebrate gamma-aminobutyric acid (GABA)ergic receptors. Because solubilized nodulisporic acid and ivermectin receptors comigrated as 230-kDa complexes by gel filtration, antisera specific for both the Drosophila glutamate-gated chloride channel subunit GluCl alpha (DmGluCl alpha) and the GABA-gated chloride channel subunit Rdl (DmRdl) proteins were generated and used to examine the possible coassembly of these two subunits within a single receptor complex. DmGluCl alpha antibodies immunoprecipitated all of the ivermectin and nodulisporic acid receptors solubilized by detergent from Drosophila head membranes. DmRdl antibodies also immunoprecipitated all solubilized nodulisporic receptors, but only approximately 70% of the ivermectin receptors. These data suggest that both DmGluCl alpha and DmRdl are components of nodulisporic acid and ivermectin receptors, and that there also exists a distinct class of ivermectin receptors that contains the DmGluCl alpha subunit but not the DmRdl subunit. This co-association of DmGluCl alpha and DmRdl represents the first biochemical and immunological evidence of coassembly of subunits from two different subclasses of ligand-gated ion channel subunits.

Animals↗

PubMed2000

Regulation of volume-activated chloride channels by P-glycoprotein: phosphorylation has the final say!

P-glycoprotein (Pgp) is a transmembrane transporter causing efflux of a number of chemically unrelated drugs and is responsible for resistance to a variety of anticancer drugs during chemotherapy. Pgp overexpression in cells is also associated with volume-activated chloride channel activity; Pgp is thought to regulate such activity. Reversible phosphorylation is a possible mechanism for regulating the transport and chloride channel regulation functions of Pgp. Protein kinase C (PKC) is a good candidate for inducing such phosphorylation. Hierarchical multiple phosphorylation (e.g. of different serines and with different PKC isoforms) may shuttle the protein between its different states of activity (transport or channel regulation). Cell volume changes may trigger phosphorylation of Pgp at sites causing inhibition of transport. The possible regulation of chloride channels by Pgp and the potential involvement of reversible phosphorylation in such regulation is reviewed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

A chloride channel reconstituted from fetal rat brain growth cones.

Chloride channels were reconstituted into planar lipid bilayers isolated from a preparation of growth cone particles (GCPs) isolated from fetal rat brain. One type of channel was predominantly seen and some of its biophysical and pharmacological properties were studied. The single channel i-V relationship was curvilinear with a chord conductance of 75 pS at +30 mV in symmetric 200 mM NaCl solutions buffered with phosphate. The channel was inactivated by depolarization, and this inactivation was reversed rapidly upon returning to -25 mV. The Cl- channel was significantly permeant to Na+ ions (PNa/PCl = 0.26), and the relative halide permeabilities were determined to be: I(1.92) > Br(1.73) > Cl(1.0) > F(0.34). The channel was inhibited by the common stilbene compounds (DIDS, SITS, DNDS), as well as by Zn2+ ions and an indanyloxyacetic acid derivative. A developmental role for the GCP Cl- channel is suggested by the observation that adult rat brain synaptosomal membranes were nearly devoid of this type of Cl- channel.

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

PubMed2000

Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a chloride channel protein that belongs to the superfamily of ATP binding cassette (ABC) transporters. Phosphorylation by protein kinase A in the presence of ATP activates the CFTR-mediated chloride conductance of the apical membranes. We have identified a novel hydrophilic CFTR binding protein, CAP70, which is also concentrated on the apical surfaces. CAP70 consists of four PDZ domains, three of which are capable of binding to the CFTR C terminus. Linking at least two CFTR molecules via cytoplasmic C-terminal binding by either multivalent CAP70 or a bivalent monoclonal antibody potentiates the CFTR chloride channel activity. Thus, the CFTR channel can be switched to a more active conducting state via a modification of intermolecular CFTR-CFTR contact that is enhanced by an accessory protein.

Amino Acid Sequence↗

PubMed2000

Overexpression of chloride channel CLC-K2 mRNA in the renal medulla of Dahl salt-sensitive rats.

OBJECTIVE: The present study aimed to characterize the influence of salt intake on the gene expression of the kidney specific chloride channels CLC-K1 and CLC-K2 in the kidneys of salt-resistant and salt-sensitive Dahl rats. DESIGN: For this purpose Dahl salt-resistant (Dahl-R) and Dahl salt-sensitive rats (Dahl-S) were fed a low (0.02%), normal (0.6%) or high (4%) salt diet for 19 days and CLC-K1 and -K2 mRNA expression was semiquantitated in cortex, outer and inner medulla. METHODS: Kidneys were macroscopically dissected, total RNA was isolated according to the guanidinium-thiocyanate-phenol-chloroform method and messenger RNAs for the kidney specific chloride channels CLC-K1 and CLC-K2 were measured by ribonuclease protection assay. RESULTS: Systolic blood pressure in high salt-treated Dahl-S rats increased to 204 +/- 5 mmHg versus 150 +/- 7 mmHg in Dahl-S controls. Dahl R and low salt Dahl-S rats showed no increase in blood pressure. For CLC-K1 mRNA we found an order of abundance inner medulla >> outer medulla >> cortex. There was no difference in mRNA abundance between Dahl-R and -S, nor any effect of the rate of salt intake on CLC-K1 mRNA abundance in the different kidney zones. CLC-K2 mRNA expression in cortex and outer medulla was similar between Dahl-R and -S rats. In the inner medulla, however, CLC-K2 mRNA was 1.7-fold higher in Dahl-S than in Dahl-R rats. In the cortex we found no influence of salt intake on CLC-K2 mRNA. In outer and inner medulla of Dahl-R rats and Dahl-S rats high salt diet led to a marked downregulation of CLC-K2 mRNA expression. Consequently, CLC-K2 gene expression in the inner medulla was 2.2-fold higher in Dahl-S than in Dahl-R rats in states of high salt diet. CONCLUSION: Given that the CLC-K2 chloride channel in the outer and inner medulla contributes to salt reabsorption, our findings would suggest that Dahl-S rats have an increased medullary salt reabsorption. This may contribute to the inability of these animals to excrete an increased salt load at a normal renal perfusion pressure leading to the development of hypertension.

Animals↗

PubMed2001

Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man.

Chloride channels play important roles in the plasma membrane and in intracellular organelles. Mice deficient for the ubiquitously expressed ClC-7 Cl(-) channel show severe osteopetrosis and retinal degeneration. Although osteoclasts are present in normal numbers, they fail to resorb bone because they cannot acidify the extracellular resorption lacuna. ClC-7 resides in late endosomal and lysosomal compartments. In osteoclasts, it is highly expressed in the ruffled membrane, formed by the fusion of H(+)-ATPase-containing vesicles, that secretes protons into the lacuna. We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis. We conclude that ClC-7 provides the chloride conductance required for an efficient proton pumping by the H(+)-ATPase of the osteoclast ruffled membrane.

Adenosine Triphosphatases↗

PubMed2005

Glycine-gated chloride channels depress synaptic transmission in rat hippocampus.

An inhibitory role for strychnine-sensitive glycine-gated chloride channels (GlyRs) in mature hippocampus is beginning to be appreciated. We have reported previously that CA1 pyramidal cells and GABAergic interneurons recorded in 3- to 4-wk-old rat hippocampal slices express functional GlyRs, dispelling previous misconceptions that GlyR expression ceases in early development. However, the effect of GlyR activation on cell excitability and synaptic circuits in hippocampus has not been fully explored. Using whole cell current-clamp recordings, we show that activation of strychnine-sensitive GlyRs through exogenous glycine application causes a significant decrease in input resistance and prevents somatically generated action potentials in both CA1 pyramidal cells and interneurons. Furthermore, GlyR activation depresses the synaptic network by reducing suprathreshold excitatory postsynaptic potentials (EPSPs) to subthreshold events in both cell types. Blockade of postsynaptic GlyRs with the chloride channel blocker 4, 4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS) or altering the chloride ion driving force in recorded cells attenuates the synaptic depression, strongly indicating that a postsynaptic mechanism is responsible. Increasing the local glycine concentration by blocking reuptake causes a strychnine-sensitive synaptic depression in interneuron recordings, suggesting that alterations in extracellular glycine will impact excitability in hippocampal circuits. Finally, using immunohistochemical methods, we show that glycine and the glycine transporter GlyT2 are co-localized selectively in GABAergic interneurons, indicating that interneurons contain both inhibitory neurotransmitters. Thus we report a novel mechanism whereby activation of postsynaptic GlyRs can function to depress activity in the synaptic network in hippocampus. Moreover, the co-localization of glycine and GABA in hippocampal interneurons, similar to spinal cord, brain stem, and cerebellum, suggests that this property is likely to be a general characteristic of inhibitory interneurons throughout the CNS.

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

PubMed1999

Inhibition of GABA-gated chloride channels by 12,14-dichlorodehydroabietic acid in mammalian brain.

1. 12,14-dichlorodehydroabietic acid (12,14-Cl2DHA) reduced GABA-stimulated uptake of 36Cl- into mouse brain synaptoneurosomes suggesting inhibition of mammalian GABA(A) receptor function. 2. 12,14-Cl2DHA did not affect the binding of [3H]-muscimol to brain membranes but displaced specifically bound [3H]-EBOB. The inhibitory effect on [3H]-EBOB binding was not reversible. 12,14-Cl2DHA reduced the availability of [3H]-EBOB binding sites (Bmax) without changing the KD of the radioligand for remaining sites. 12,14-Cl2DHA did not affect the rate of association of [3H]-EBOB with its chloride channel receptor, but increased the initial rate of [3H]-EBOB dissociation. 3. 12,14-Cl2DHA enhanced the incidence of EPSCs when rapidly applied to cultured rat cortical neurones. Longer exposures produced block of IPSCs with marked increases in the frequency of EPSCs and min EPSCs. 12,14-Cl2DHA also irreversibly suppressed chloride currents evoked by pulses of exogenous GABA in these cells. 4. Ultimately, 12,14-Cl2DHA inhibited all synaptic traffic and action currents in current clamped cells indicating that, in contrast to picrotoxinin (which causes paroxysmal bursting), it is not fully selective for the GABA(A) receptor-chloride channel complex. 5. The depolarizing block seen with 12,14-Cl2DHA in amphotericin-perforated preparations implicates loss of Ca2+ buffering in the polarity change and this may account for inhibition of spontaneous action potentials. 6. Our investigation demonstrates that 12,14-Cl2DHA blocks GABA-dependent chloride entry in mammalian brain and operates as a non-competitive insurmountable GABA(A) antagonist. The mechanism likely involves either irreversible binding of 12,14-Cl2DHA to the trioxabicyclooctane recognition site or a site that is allosterically coupled to it. We cannot exclude, however, the possibility that 12,14-Cl2DHA causes localized proteolysis or more extensive conformational change within a critical subunit of the chloride channel.

Abietanes↗

PubMed2000

Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocytes.

The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its well defined Cl(-) channel properties, regulates other ion channels. CFTR inhibits epithelial Na(+) channel (ENaC) currents in many epithelial and nonepithelial cells. Because modulation of net NaCl reabsorption has important implications in extracellular fluid volume homeostasis and airway fluid volume and composition, we investigated whether this regulation was reciprocal by examining whether ENaC regulates CFTR. Co-expression of human (h) CFTR and mouse (m) alphabetagammaENaC in Xenopus oocytes resulted in a significant, 3.7-fold increase in whole-cell hCFTR Cl(-) conductance compared with oocytes expressing hCFTR alone. The forskolin/3-isobutyl-1-methylxanthine-stimulated whole-cell conductance in hCFTR-mENaC co-injected oocytes was amiloride-insensitive, indicating an inhibition of mENaC following hCFTR activation, and it was blocked by DPC (diphenylamine-2-carboxylic acid) and was DIDS (4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid)-insensitive. Enhanced hCFTR Cl(-) conductance was also observed when either the alpha- or beta-subunit of mENaC was co-expressed with hCFTR, but this was not seen when CFTR was co-expressed with the gamma-subunit of mENaC. Single Cl(-) channel analyses showed that both CFTR Cl(-) channel open probability and the number of CFTR Cl(-) channels detected per patch increased when hCFTR was co-expressed with alphabetagammamENaC. We conclude that in addition to acting as a regulator of ENaC, CFTR activity is regulated by ENaC.

Animals↗

PubMed2004

Calcium-activated chloride channel-2 in human epithelia.

Calcium-activated chloride channels (CLCAs) are a family of multifunctional proteins that are widely distributed in tissues. To investigate the distribution of human CLCA-2 (hCLCA2) in human epithelia at the light and electron microscopic levels, we raised a primary antibody against a synthetic polypeptide sequence from natural hCLCA2. Corneal, skin, vaginal, esophageal, and laryngeal epithelia were immunopositive for hCLCA2 at the cytosolic aspect of the basal cells adjacent to the basement membrane. Epithelia of stomach and small intestine showed no hCLCA2 immunoreactivity. This study reports the cellular distribution of hCLCA2 in human epithelia and suggests its possible involvement in epithelial stratification and cell-substrate adhesion.

Chloride Channels↗

PubMedDate not supplied

An increase in [Ca2+]i activates basolateral chloride channels and inhibits apical sodium channels in frog skin epithelium.

The aim of this study was to investigate the mechanisms by which increases in free cytosolic calcium ([Ca2+]i) cause a decrease in macroscopic sodium absorption across principal cells of the frog skin epithelium. [Ca2+]i was measured with fura-2 in an epifluorescence microscope set-up, sodium absorption was measured by the voltage-clamp technique and cellular potential was measured using microelectrodes. The endoplasmic reticulum calcium-ATPase inhibitor thapsigargin (0.4 microM) increased [Ca2+]i from 66 +/- 9 to 137 +/- 19 nM (n = 13, P = 0.002). Thapsigargin caused the amiloride-sensitive short circuit current (Isc) to drop from 26.4 to 10.6 microA cm-2 (n = 19, P<0.001) concomitant with a depolarization of the cells from -79 +/- 1 to -31 +/- 2 mV (n = 18, P<0.001). Apical sodium permeability (PaNa) was estimated from the current/voltage (I/V) relationship between amiloride-sensitive current and the potential across the apical membrane. PaNa decreased from 8.01.10(-7 )to 3.74.10(-7) cm s-1 (n = 7, P = 0.04) following an increase in [Ca2+]i. A decrease in apical sodium permeability per se would tend to decrease Isc and result in a hyperpolarization of the cell potential and not, as observed, a depolarization. Serosal addition of the chloride channel inhibitors 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), diphenylamine-2-carboxylate (DPC), indanyloxyacetic acid 94 (IAA-94) and furosemide reversed the depolarization induced by thapsigargin, indicating that chloride channels were activated by the increase in [Ca2+]i. This was confirmed in wash-out experiments with 36Cl where it was shown that thapsigargin increased the efflux of chloride from 32.49 +/- 5.01 to 62.63 +/- 13.3 nmol.min-1 cm-2 (n = 5, P = 0.04). We conclude that a small increase in [Ca2+]i activates a chloride permeability and inhibits the apical sodium permeability. The activation of chloride channels and the closure of apical sodium channels will tend to lower the macroscopic sodium absorption.

Animals↗

PubMed2003

Electrostatic control and chloride regulation of the fast gating of ClC-0 chloride channels.

The opening and closing of chloride (Cl-) channels in the ClC family are thought to tightly couple to ion permeation through the channel pore. In the prototype channel of the family, the ClC-0 channel from the Torpedo electric organ, the opening-closing of the pore in the millisecond time range known as "fast gating" is regulated by both external and internal Cl- ions. Although the external Cl- effect on the fast-gate opening has been extensively studied at a quantitative level, the internal Cl- regulation remains to be characterized. In this study, we examine the internal Cl- effects and the electrostatic controls of the fast-gating mechanism. While having little effect on the opening rate, raising [Cl-]i reduces the closing rate (or increases the open time) of the fast gate, with an apparent affinity of >1 M, a value very different from the one observed in the external Cl- regulation on the opening rate. Mutating charged residues in the pore also changes the fast-gating properties-the effects are more prominent on the closing rate than on the opening rate, a phenomenon similar to the effect of [Cl-]i on the fast gating. Thus, the alteration of fast-gate closing by charge mutations may come from a combination of two effects: a direct electrostatic interaction between the manipulated charge and the negatively charged glutamate gate and a repulsive force on the gate mediated by the permeant ion. Likewise, the regulations of internal Cl- on the fast gating may also be due to the competition of Cl- with the glutamate gate as well as the overall more negative potential brought to the pore by the binding of Cl-. In contrast, the opening rate of the fast gate is only minimally affected by manipulations of [Cl-]i and charges in the inner pore region. The very different nature of external and internal Cl- regulations on the fast gating thus may suggest that the opening and the closing of the fast gate are not microscopically reversible processes, but form a nonequilibrium cycle in the ClC-0 fast-gating mechanism.

Animals↗

PubMed1995

Drug-transport and volume-activated chloride channel functions in human erythroleukemia cells: relation to expression level of P-glycoprotein.

The characteristics of volume-activated chloride currents, drug transport function and levels of P-glycoprotein (PgP) expression were compared between two human chronic erythroleukemia cell lines: a parental (K562) cell line and a derivative obtained by vinblastine selection (K562 VBL400). Parental K562 cells showed no detectable P-glycoprotein expression, measured at the protein level (immunofluorescence labeling with monoclonal antibodies), and had very low levels of MDR-1 mRNA expression (RT-PCR analysis), when compared with levels measured in K562 VBL400. Differences in Pgp-mediated transport were estimated by comparing the rates of Fluo3 accumulation. The higher drug-transport function of K562 VBL400 cells (e.g., lower Fluo3 accumulation) correlated with their elevated levels of MDR-1. The rate of dye transport was sensitive to verapamil but was not affected by the tonicity of the extracellular medium. In contrast to the clear differences in transport function, the characteristics of chloride currents induced by cell swelling were indistinguishable between the two cell lines. Currents measured in the whole-cell configuration were outwardly rectifying, had a higher permeability to iodide than to chloride (SCN- > I- > Cl- > gluconate), were potently blocked by NPPB and were unresponsive to verapamil. The percentage of responding cells and the mean current density were nearly identical in both cell lines. In addition, activation of the volume-sensitive current was not prevented during whole-cell recordings obtained with pipettes containing high concentration of cytotoxic drugs (vincristine or vinblastine). These results do not lend support to the previously reported association between Pgp expression and volume-sensitive chloride channels, and suggest that a different protein is responsible for this type of chloride channel in K562 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1991

GABA accelerates excitotoxic cell death in cortical cultures: protection by blockers of GABA-gated chloride channels.

The effects of gamma-aminobutyric acid (GABA) and related agonists and antagonists on the excitatory cell death were examined in dispersed primary cultures of the rat cerebral cortex. The cytotoxic effects evoked by kainic acid, quisqualic acid and N-methyl-D-aspartic acid were evaluated by phase contrast microscopy and quantified by the measurement of lactic dehydrogenase release into the culture medium. GABA accelerated the cell death in a concentration-dependent fashion, but did not influence the amount of cells dying with 24 h after the treatment. This effect of GABA could be mimicked by GABAA rather than GABAB receptor agonists. Blockers acting at different sites of the GABAA receptor/chloride channel complex not only reduced the GABA-induced acceleration of cell death, but also showed a significant protection against the excitotoxic cell death in the absence of exogenous GABA. Blockers of chloride channels unrelated to GABA receptors produced similar protection. Our findings indicate that GABA-gated chloride channels may be effective in modulating excitotoxic vulnerability of cerebrocortical cells.

Animals↗