[Changes in the density of GABAA receptor chloride channels in rodent brain induced by norbornane].
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Acylation↗
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Terbium modulation of single gamma-aminobutyric acid-activated chloride channels in rat dorsal root ganglion neurons.
We have previously reported that lanthanides markedly potentiate the GABA-induced chloride current by acting at a distinct site on the GABAA receptor-channel complex (Ma and Narahashi, 1993a,b). These studies have now been extended to the single-channel level and changes in gating kinetics of GABAA receptor currents caused by 100 microM terbium (Tb3+) are reported. The GABA-induced currents were recorded from outside-out membrane patches isolated from rat dorsal root ganglion neurons in primary culture at a holding potential of -60 mV. At least two conductance levels were recorded, a main conductance of about 26 pS (70-80% of events) and a subconductance of about 19 pS (20-30% of events). These two conductances and the ratio of main- and subconductance state currents with respect to the number of events were not changed by Tb3+. The frequency of channel openings was also unchanged in the presence of Tb3+. The frequency histograms of open, close, and burst durations of the main-conductance state were best fitted by a sum of three exponential functions. All of the time constants remained unchanged by application of Tb3+ while the relative proportions of the longest open and burst duration time constants were increased and the relative proportion of longest closed time constant was decreased. We suggest that Tb3+ binds to an allosteric site on the GABAA receptor-channel complex to increase the apparent mean open time of the channel by increasing the affinity of GABA for the GABA binding site, and/or by shifting the distribution toward the open states so that the frequency of occurrence of longer open states is stabilized.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Inhibition of collateral artery growth by mibefradil: possible role of volume-regulated chloride channels.
Endothelial cell swelling is one of the earliest hallmarks of arteriogenesis, the growth and maturation of collaterals. Mibefradil was found to block endothelial Cl(-) channels that control the volume of endothelial cells. Thus the authors investigated whether the blockade of volume-controlling endothelial cell channels would translate into an inhibition of arteriogenesis. In BALB/c mice, the right femoral artery was ligated and the animals received either mibefradil or solvent (phosphate-buffered saline [PBS]) via osmotic minipumps. Laser Doppler perfusion ratio (R/L) of ligated versus nonligated distal hindlimb increased from 0.06 +/- 0.01 (immediately after ligation) to 0.25 +/- 0.02 (day 7) in the PBS group and only from 0.07 +/- 0.02 to 0.13 +/- 0.02 in the mibefradil group (p <.01). Collateral artery diameters were significantly smaller in the mibefradil group (61 +/- 4.7 microm) versus controls (77.3 +/- 0.9 microm) (p <.05). Relative hemoglobin oxygen saturation measurements confirmed these findings (p <.02). The inhibition of arteriogenesis in the mibefradil group suggests that endothelial Cl(-) channels are involved in the initiation of arteriogenesis.
Animals↗
Extracellular zinc ion inhibits ClC-0 chloride channels by facilitating slow gating.
Extracellular Zn2+ was found to reversibly inhibit the ClC-0 Cl- channel. The apparent on and off rates of the inhibition were highly temperature sensitive, suggesting an effect of Zn2+ on the slow gating (or inactivation) of ClC-0. In the absence of Zn2+, the rate of the slow-gating relaxation increased with temperature, with a Q10 of approximately 37. Extracellular Zn2+ facilitated the slow-gating process at all temperatures, but the Q10 did not change. Further analysis of the rate constants of the slow-gating process indicates that the effect of Zn2+ is mostly on the forward rate (the rate of inactivation) rather than the backward rate (the rate of recovery from inactivation) of the slow gating. When ClC-0 is bound with Zn2+, the equilibrium constant of the slow-gating process is increased by approximately 30-fold, reflecting a 30-fold higher Zn2+ affinity in the inactivated channel than in the open-state channel. As examined through a wide range of membrane potentials, Zn2+ inhibits the opening of the slow gate with equal potency at all voltages, suggesting that a two-state model is inadequate to describe the slow-gating transition. Following a model originally proposed by Pusch and co-workers (Pusch, M., U. Ludewig, and T.J. Jentsch. 1997. J. Gen. Physiol. 109:105-116), the effect of Zn2+ on the activation curve of the slow gate can be well described by adding two constraints: (a) the dissociation constant for Zn2+ binding to the open channel is 30 microM, and (b) the difference in entropy between the open state and the transition state of the slow-gating process is increased by 27 J/ mol/ degreesK for the Zn2+-bound channel. These results together indicate that extracellular Zn2+ inhibits ClC-0 by facilitating the slow-gating process.
Animals↗
Inhibition of sodium current by chloride channel blocker 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) in guinea pig cardiac ventricular cells.
The effects of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), a potent anion transport blocker, on transmembrane action potentials (APs) and the sodium current (I[Na]) of guinea pig ventricular myocytes were examined by using conventional microelectrode and whole-cell patch-clamp recording techniques. In papillary muscle preparations, DIDS (> or =0.1 mM) suppressed the maximal upstroke velocity (.v[max]) of the AP without significant changes in other AP parameters. Extracellular application of DIDS on single cardiomyocytes isolated from the guinea pig ventricle markedly reduced the peak amplitude of the tetrodotoxin (TTX)-sensitive and voltage-activated sodium current. The concentration-dependent block of DIDS could be expressed by the Hill equation with a Hill coefficient of 0.97 and a dissociation constant of 0.15 mM at a holding potential of (VH) -120 mV. DIDS (0.1 mM) shifted the steady-state inactivation curve for I(Na) toward more negative potentials by 6.0 +/- 0.5 mV and the activation curve to more positive potentials by 5.0 +/- 1.0 mV, although the slope factors were unaffected. With repetitive depolarizing pulses from -120 mV, DIDS produced a use-dependent block on the I(Na). Recovery of I(Na) from inactivation was slowed (time constant = 245 ms, compared with 10 ms of control) in the presence of 0.1 mM DIDS. In the two-pulse experiments, DIDS produced two distinct phases of development of I(Na) block, the rapid phase (tau = 5 ms) caused by an open channel block, and the slower phase (tau = 382 ms) induced by an inactivated channel block. These results suggest that the Cl- transport blocker DIDS has a direct inhibitory effect on the cardiac sodium channel. DIDS-induced use dependence of I(Na) block may result from the interaction of the drug with sodium channels in both the open and inactivated channel states.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
The affinity of cyclodepsipeptides to the brain chloride channel domain of the GABAA receptor in vitro.
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Animals↗
Biochemical and biophysical identification of cystic fibrosis transmembrane conductance regulator chloride channels as components of endocytic clathrin-coated vesicles.
Cystic fibrosis results from mutations in the gene encoding the CFTR Cl- channel. Although CFTR occurs as an integral component of the plasma membrane, recent studies implicate CFTR in endocytic recycling and suggest that the protein may also exist in intracellular vesicular compartments. To test this, we analyzed CFTR in clathrin-coated vesicles (CCV) purified from cells constitutively expressing CFTR at high levels. CFTR immunoreactivity was detected in CCV by immunoblot and was identified as CFTR based on labeling of immunoprecipitates with protein kinase A and by tryptic phosphopeptide mapping. Fusion of uncoated CCV with planar lipid bilayers resulted in the incorporation of kinase- and ATP-activated Cl- channel activity (7.8 pS at 20 degrees C; 11.9 pS at 37 degrees C), with a linear current-voltage relation under symmetrical conditions. Thus, functional CFTR occurs in CCV. Moreover, CFTR interacts with the plasma membrane specific adaptor complex during endocytosis through clathrin-coated pits. Therefore, the abundance of CFTR in the plasma membrane may be regulated by exocytic insertion and endocytic recycling, and these processes may provide an augmentation to protein kinase A activation as a mechanism for regulating CFTR Cl channels in the plasma membrane.
Amino Acid Sequence↗
Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla.
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Amino Acid Sequence↗
Thyroid hormone modulates ClC-2 chloride channel gene expression in rat renal proximal tubules.
Thyroid hormones has its main role in controlling metabolism, but it can also modulate extracellular fluid Volume (ECFV) through its action on the expression and activity of Na(+) transporters. Otherwise, chloride is the main anion in the ECFV and the influence of thyroid hormones in the regulation of chloride transporters is not yet understood. In this work, we studied the effect of thyroid hormones in the expression of ClC-2, a cell Volume-, pH- and voltage-sensitive Cl(-) channel, in rat kidney. To analyze the modulation of ClC-2 gene expression by thyroid hormones, we used hypothyroid (Hypo) rats with or without thyroxine (T(4)) replacement and hyperthyroid (Hyper) rats as our experimental models. Total RNA was isolated and the expression of ClC-2 mRNA was evaluated by a ribonuclease protection assay, and/or semi-quantitative RT-PCR. Renal ClC-2 expression decreased in Hypo rats and increased in Hyper rats. In addition, semi-quantitative RT-PCR of different nephron segments showed that these changes were due exclusively to the modulation of ClC-2 mRNA expression by thyroid hormone in convoluted and straight proximal tubules. To investigate whether thyroid hormones action was direct or indirect, renal proximal tubule primary culture cells were prepared and subjected to different T(4) concentrations. ClC-2 mRNA expression was increased by T(4) in a dose-dependent fashion, as analyzed by RT-PCR. Western blotting demonstrated that ClC-2 protein expression followed the same profile of mRNA expression.
Animals↗
A cAMP-activated chloride channel in the plasma membrane of cultured human gastric cells (HGT-1).
Hydrochloric acid (HCl) secretion by gastric parietal cells involves an apical Cl- conductance, the properties of which have not been defined. In the present study, forskolin and histamine [agonists that increase intracellular cyclic adenosine monophosphate (cAMP)], and dibutyryl cAMP, activated channels in previously quiescent cell-attached membrane patches on cultured human gastric cells (HGT-1). In the cell-attached configuration (Cl- 149 mmol/l in bath and pipette), channels exhibited outward rectification, voltage dependence, inward current (-0.7 pA) at zero holding potential and a reversal potential of +24 mV, consistent with the presence of a Cl- conductive pathway. In excised inside-out patches, channels (i) exhibited degrees of outward rectification and voltage dependence that were comparable to those seen in cell-attached patches, (ii) demonstrated a -21 mV shift of their reversal potential when bath Cl- was decreased from 149 mmol/l to 53 mmol/l (calculated Cl-:cation permeability ratio 17:1), and (iii) were highly sensitive to the Cl- channel blocker diphenylamine-2-carboxylic acid (DPC, 10(-3) mol/l). This cAMP-activated Cl- channel bears many similarities to other Cl- channels within intestinal epithelia, and may represent the apical Cl- channel operating in HCl-secreting gastric parietal cells.
Adenocarcinoma↗
Nucleoside triphosphates are required to open the CFTR chloride channel.
The CFTR Cl- channel contains two predicted nucleotide-binding domains (NBD1 and NBD2); therefore, we examined the effect of ATP on channel activity. Once phosphorylated by cAMP-dependent protein kinase (PKA), channels required cytosolic ATP to open. Activation occurred by a PKA-independent mechanism. ATP gamma S substituted for ATP in PKA phosphorylation, but it did not open the channel. Several hydrolyzable nucleotides (ATP greater than GTP greater than ITP approximately UTP greater than CTP) reversibly activated phosphorylated channels, but nonhydrolyzable analogs and Mg(2+)-free ATP did not. Studies of CFTR mutants indicated that ATP controls channel activity independent of the R domain and suggested that hydrolysis of ATP by NBD1 may be sufficient for channel opening. The finding that nucleoside triphosphates regulate CFTR begins to explain why CF-associated mutations in the NBDs block Cl- channel function.
Adenosine Triphosphate↗
Nonlinear amplification by calcium-dependent chloride channels in olfactory receptor cells.
The sense of smell is highly evolved in mammals, allowing discrimination between a vast number of odorants, with detection thresholds as low as 10(-17) M (ref. 1). Although several features of mammalian olfactory transduction have been revealed by biochemical and molecular biological studies, the odorant-induced membrane current has remained elusive. In amphibians this current is mediated by cyclic-nucleotide-gated channels, which depolarize the cell by Na+ and Ca+ influx and consequent Cl- efflux through Ca(2+)-dependent Cl- channels. The Cl- current may be absent in mammals, however, because its proposed role is linked to the aquatic habitat of amphibians. Here we show that the transduction current in rat olfactory receptor cells is initiated by cyclic-nucleotide-gated channels. The Cl- current is also present and endows the transduction current with a steep sigmoidal dependence on cyclic AMP concentration in both rat and in an amphibian, indicating a new function for the Cl- channel: nonlinear amplification of the transduction signal, whereby suprathreshold responses are boosted relative to basal transduction noise.
Amphibians↗
Amazing chloride channels: an overview.
AIM: This review describes molecular and functional properties of the following Cl- channels: the ClC family of voltage-dependent Cl- channels, the cAMP-activated transmembrane conductance regulator (CFTR), Ca2+ activated Cl- channels (CaCC) and volume-regulated anion channels (VRAC). If structural data are available, their relationship with the function of Cl- channels will be discussed. We also describe shortly some recently discovered channels, including high conductance Cl- channels and the family of bestrophins. We illustrate the growing physiological importance of these channels in the plasma membrane and in intracellular membranes, including their involvement in transepithelial transport, pH regulation of intracellular organelles, regulation of excitability and volume regulation. Finally, we discuss the role of Cl- channels in various diseases and describe the pathological phenotypes observed in knockout mice models.
Animals↗
ATP-activated chloride channel inhibited by an antibody to P glycoprotein.
In this report, we present the characteristics of a Cl- channel found in lens fiber cells. The single channel has a conductance of 17 pS, a linear current-voltage curve, is activated by ATP or strong depolarization and is blocked by verapamil, quinidine, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, 5-nitro-2-(3- phenylpropylamino)benzoate, dideoxyforskolin, and tamoxifen. These properties are similar to those reported for a volume-activated Cl- channel associated with the multidrug resistance (MDR) gene product, P glycoprotein (24). Confirming this connection, we demonstrate that our lens Cl- channel is inhibited by an antibody to P glycoprotein. The data we present here may, therefore, be the first characterization of the single channel activity of the Cl- channel associated with P glycoprotein.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Chloride channel inhibition prevents ROS-dependent apoptosis induced by ischemia-reperfusion in mouse cardiomyocytes.
Apoptosis of cardiomyocytes following ischemia and reperfusion is of clinical importance. However, little is known about the mechanism by which it is induced. Recently, essential roles of a Cl- channel whose activity triggers the apoptotic volume decrease and of reactive oxygen species (ROS) in activation of this channel have been identified in mitochondrion-mediated apoptosis. Therefore, in this study, involvement of Cl- channels and ROS in apoptosis was studied in primary mouse cardiomyocyte cultures subjected to ischemia-reperfusion. Apoptotic cell death as measured by caspase-3 activation, chromatin condensation, DNA laddering, and cell viability reduction was observed tens of hours after reperfusion but never immediately after ischemia. A non-selective Cl-channel blocker (DIDS or NPPB) rescued cells from apoptotic death when applied during the reperfusion, but not ischemia, period. Another blocker relatively specific to the volume-sensitive outwardly rectifying (VSOR) Cl-channel (phloretin) was also effective in protecting ischemic cardiomyocytes from apoptosis induced by reperfusion. A profound increase in intracellular ROS was detected in cardiomyocytes during the reperfusion, but not ischemia, period. Scavengers for ROS, H2O2 and superoxide all inhibited apoptosis induced by ischemia-reperfusion. Thus, it is concluded that the mechanism by which cardiomyocyte apoptosis is induced by ischemia-reperfusion involves VSOR Cl- channel activity and intracellular ROS production.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Cardiac sarcoplasmic reticulum chloride channels regulated by protein kinase A.
In heart cells, several plasma membrane ion channels are targets for phosphorylation. However, it is not known whether sarcoplasmic reticulum (SR) ion channels, which are also essential in the regulation of cardiac function, are regulated by second-messenger systems. Here, we show that a Cl- channel in the cardiac SR membrane is activated by the catalytic subunit of protein kinase A (PKA). Purified cardiac heavy SR vesicles were incorporated into planar lipid bilayers. This channel spontaneously inactivated within a few minutes after the channel was incorporated into the bilayer. Mg-ATP (2-5 mM), but not the nonhydrolyzable ATP analogue 5'-adenylylimidodiphosphate, added to the cis solution prevented this spontaneous channel inactivation. After the inactivation process occurred, the catalytic subunit of PKA (with 0.05 mM Mg-ATP) reactivated this channel. These effects of Mg-ATP and PKA on the Cl- channel were prevented by an inhibitor of PKA. Thus, these results suggest that this SR Cl- channel is a novel target of PKA-dependent phosphorylation in cardiac muscle regulation.
Adenosine Triphosphate↗
Chloride channels in apical membrane patches of stellate cells of Malpighian tubules of Aedes aegypti.
Stellate cells of Aedes aegypti Malpighian tubules were investigated using patch-clamp methods to probe the route of transepithelial Cl(-) secretion. Two types of Cl(-) channel were identified in excised, inside-out apical membrane patches. The first Cl(-) channel, type I, had a conductance of 24 pS, an open probability of 0.816+/-0.067, an open time of 867+/-114 ms (mean +/- s.e.m., four patches) and the selectivity sequence I(-)>Cl(-)(much greater than) isethionate>gluconate. The I(-)/Cl(-)>>isethionate>gluconate. The I(-)Cl(-) permeability ratio was 1.48, corresponding to Eisenman sequence I. The type I Cl(-) channel was blocked by 2,2'-iminodibenzoic acid (DPC) and niflumic acid (2-[3-(trifluoromethyl)anilo]nicotinic acid). The removal of Ca(2+) from the Ringer's solution on the cytoplasmic side had no effect on channel activity. The second Cl(-) channel, type II, had a conductance of 8 pS, an open probability of 0.066+/-0.021 and an open time of 7.53+/-1.46 ms (mean +/- s.e.m., four patches). The high density and halide selectivity sequence of the type I Cl(-) channel is consistent with a role in transepithelial Cl(-) secretion under control conditions, but it remains to be determined whether these Cl(-) channels also mediate transepithelial Cl(-) secretion under diuretic conditions in the presence of leucokinin.
Aedes↗
Chloride channels: a molecular perspective.
Plasma membrane Cl- channels perform a variety of functions, including control of excitability in neurons and muscle, cell volume regulation and transepithelial transport. Structurally, three classes of Cl- channels have been identified: ligand-gated, postsynaptic Cl- channels (e.g. GABA and glycine receptors); the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels (which belong to the traffic ATPase superfamily); and the CLC family of Cl- channels. Recent developments of note include further characterization of the expanding CLC Cl- channel family, advances in understanding the regulation of the CFTR Cl- channel and its emergent role as a regulator of other channels, clarification of issues related to swelling-activated Cl- channels, and the discovery that several co-transporter molecules are now known to induce Cl- currents in Xenopus oocytes.
Animals↗