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At least 883 records · Page 49Linked to original sources
PubMed2000

Chloride channels in toad skeletal muscle fibers.

Chloride currents were measured in short lumbricalis fibers of toads (Bufo arenarum) with voltage and patch clamp techniques. For the availability of chloride currents we applied a double-pulse technique in voltage-clamped fibers. When the test pulse was preceded by a positive prepulse, the initial current was larger than with a negative prepulse and exhibited a different rate of decline to its steady-state value. At the single-channel level we found that in most of the experiments with symmetrical 110 mM NaCl solutions, two levels of conductance, 20 ("small channel") and 360 pS ("maxi channel"), occurred with the highest probabilities. The openings of the maxi channels were more frequent at potentials close to 0 mV, whereas for the small channels the openings were at negative potentials. In contrast with the results with the macroscopic currents, a change of 2 orders of magnitude in the pH, from 7.3 to 5, had only minor effects on the channels' conductance. As with some other anion channels, the selectivity of the channels described here is low, the p(Cl)/p(Na) ratio being 1.9 and 3.7 for the small and maxi Cl(-) channels, respectively. The behavior of these Cl(-) channels with a relative high Na(+) permeability could contribute to the relatively low resting membrane potential of the lumbricalis fibers measured in the standard 110 mM NaCl solution.

Animals↗
PubMed2003

Chloride channels in basolateral TAL membranes. XVIII. Phenylglyoxal induces functional mcCIC-Ka activity in basolateral MTAL membranes.

Cultured mouse MTAL cells contain more mRNA encoding the Cl- channel mcCIC-Ka, which mediates CTAL Cl- absorption, than mRNA encoding the Cl- channel mmCIC-Ka, which mediates MTAL Cl- absorption. mmCIC-Ka and mcCIC-Ka have three functional differences: 1) mmCIC-Ka open time probability, Po, increases with increasing cytosolic Cl-, but variations in cytosolic Cl- do not affect Po in mcCIC-Ka; 2) mmCIC-Ka is gated by (ATP + PKA), while (ATP + PKA) have no effect on Po in mcCIC-Ka; and 3) mmCIC-Ka channels have single-ion occupancy, while mcCIC-Ka channels have multi-ion occupancy. Using basolateral vesicles from MTAL cells fused into bilayers, we evaluated the effects of 1 mM cytosolic phenylglyoxal (PGO), which binds covalently to lysine or arginine, on Cl- channels. With PGO pretreatment, Cl- channels were uniformly not gated either with increases in cytosolic-face Cl- or with (ATP + PKA) at 2 mM cytosolic-face Cl-; and they exhibited multi-ion occupancy kinetics typical for mcCIC-Ka channels. Thus, in basolateral MTAL membranes, blockade of Cl- access to arginine or lysine residues on mmCIC-Ka by PGO results in Cl- channels having the functional characteristics of mcCIC-Ka channels.

Adenosine Triphosphate↗
PubMed1987

Receptors for gamma-aminobutyric acid and voltage-dependent chloride channels as targets for drugs and toxicants.

The function of chloride (Cl-) channel proteins is to regulate the transport of Cl- across membranes. There are two major kinds of Cl- channels: 1) those activated by binding of a transmitter such as gamma-aminobutyric acid (GABA), glycine, or glutamate, and thus are receptors; and 2) those activated by membrane depolarization or by calcium. There are two kinds of GABA receptors: GABAA is the major inhibitory receptor of vertebrate brain and the one that operates a Cl- channel, and the GABAB receptor, which is proposed to regulate cAMP production that is stimulated by other receptors. Except for binding of GABA, these two GABA receptors differ completely in their drug specificities. However, there are many similarities among the GABAA receptor, the glycine receptor, and the voltage-dependent Cl- channel. The two receptors and Cl- channels bind avermectin, whereas bicuculline binds only to mammalian GABAA and glycine receptors, not to the insect brain GABAA receptor. Barbiturates bind to GABAA and voltage-dependent Cl- channels, possibly directly activating them. Benzodiazepines potentiate both the glycine and GABAA receptors. Several insecticides act on the GABAA receptor and voltage-dependent Cl- channel. It is suggested that the GABAA receptor is the primary target for the action of toxaphene and cyclodiene insecticides but a secondary target for lindane and type II pyrethroids. On the other hand, the Cl- channel may be a primary target for avermectin and lindane but a secondary one for cyclodienes. The similarity in certain drug specificities and the operation of Cl- channels suggest a degree of homology between the subunits of GABAA and glycine receptors and the voltage-dependent Cl- channels.

Animals↗
PubMed2001

Chloride channels and their functional roles in smooth muscle tone in the vasculature.

Although evidence of important contributions by Cl- channels to agonist-induced currents have been reported in vascular smooth muscle cells, the functional roles played by Cl- channels in the smooth muscle contraction and in setting the membrane potential remain essentially obscure. All of the admittedly few papers published have focused on the physiological roles of Cl- channels in the contraction and membrane depolarization elicited by agonists. At present, it seems likely that in vascular cells: a) Cl- conductance contributes to membrane depolarization, with the subsequent contraction being due to Ca2+ release from the intracellular store sites, and b) Cl- movements through the membrane of the Ca2+ store sites also regulate Ca2+ release and Ca2+ uptake from/into the store sites. As a Ca2+-dependent Cl- current is most easily demonstrated under quasi-physiological conditions (by the perforated patch-clamp method), the contribution made by Cl- channels to smooth muscle function may be more important than previously thought. The development of the new, selective Cl--channel blockers as well as the identification and gene engineering of the channel molecules are essential if we are to advance our knowledge of the physiology and pharmacology of the Cl- channels residing in vascular smooth muscle cells.

Animals↗
PubMed1996

Mechanism of voltage-dependent gating in skeletal muscle chloride channels.

Voltage-dependent gating was investigated in a recombinant human skeletal muscle Cl- channel, hCIC-1, heterologously expressed in human embryonic kidney (HEK-293) cells. Gating was found to be mediated by two qualitatively distinct processes. One gating step operates on a microsecond time scale and involves the rapid rearrangement of two identical intramembranous voltage sensors, each consisting of a single titratable residue. The second process occurs on a millisecond time scale and is due to a blocking-unblocking reaction mediated by a cytoplasmic gate that interacts with the ion pore of the channel. These results illustrate a rather simple structural basis for voltage sensing that has evolved in skeletal muscle Cl- channels and provides evidence for the existence of a cytoplasmic gating mechanism in an anion channel analogous to the "ball and chain" mechanism of voltage-gated cation channels.

Animals↗
PubMed1990

Factors affecting actions of ethanol on GABA-activated chloride channels.

Effects of ethanol in vitro on membrane vesicles (microsacs prepared from mouse cerebral cortex) were evaluated by monitoring 36Cl- influx. Different assay parameters were tested to determine increased or decreased action of ethanol on GABA-activated chloride channels. The ability of 30 mM ethanol to augment 36Cl- flux was seen at 0 degrees C, in the absence of GABA ("direct" action of ethanol), and at 34 degrees C in the presence of GABA, using two different assay procedures. Picrotoxin blocked the direct effects of ethanol (at 0 degrees C) suggesting GABAa involvement. Endogenous GABA in the medium surrounding the microsacs was assayed at different temperatures both in the presence and absence of GABA and ethanol. The direct effect of ethanol did not appear to involve the action of endogenous GABA. In addition to temperature effects on the assay, time of membrane storage also influenced ethanol action. Microsacs stored on ice for 2 hours or more lost their ability to respond to ethanol but not to GABA, pentobarbital or flunitrazepam. When these drugs were tested on membranes from mice that had been sacrificed by cervical dislocation as opposed to decapitation, ethanol did not augment GABA-stimulated chloride flux. The method of sacrifice did not influence the response to GABA, pentobarbital or flunitrazepam.

Animals↗
PubMed1992

Outwardly rectifying chloride channels in lymphocytes.

Outwardly rectifying Cl- channels in cultured human Jurkat T-lymphocytes were activated by excising a patch of membrane using the inside-out (i/o) patch-clamp configuration and holding at depolarized voltages for prolonged periods of time (1-6 min at +80 mV, 20 degrees C). The single-channel current at +80 mV was 4.5 +/- 0.3 pA and at -80 mV, it was 1.0 +/- 0.4 pA. After activation, the probability of being open (Po) for the lymphocyte channel was voltage independent. Activation of the Cl- channel in lymphocytes was temperature dependent. Nineteen percent of i/o recordings from lymphocytes made at 20 degrees C exhibited Cl- channel activity. In contrast, 49% of recordings made at 30 degrees C showed channel activity. The number of channels in an active patch was not significantly different at the two temperatures. Channel activation in excised, depolarized patches also occurred 20-fold faster at 30 degrees C than at 20 degrees C. There was no marked change in the single-channel conductance at 30 degrees C. Open-channel conductance was blocked by 200 microM indanyloxyacetic acid (IAA) or 1 mM SITS when applied to the intracellular side of the patch. The characteristics of this channel are similar to epithelial outwardly rectifying Cl- channels thought to be involved in fluid secretion.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1990

Direct modulation of secretory chloride channels by arachidonic and other cis unsaturated fatty acids.

The effect of fatty acids on Cl- channels and transepithelial Cl- secretion is investigated. Patch-clamp experiments show that arachidonic acid blocks Cl- channels in a dose-dependent manner. Kinetic analysis shows that the mean open time is decreased 10-fold with 25 microM arachidonic acid. There is a linear relationship between the reciprocal of mean open time and blocker concentration within the range of 1 to 25 microM. The reciprocal of mean blocked time does not change with arachidonic acid concentration. Other cis unsaturated fatty acids, including oleic, linoleic, and ricinoleic acids, demonstrate similar blocks. Trans unsaturated acids such as elaidic acid and saturated fatty acids, including stearic, palmitic, and myristic acids, do not inhibit the channel at 20 microM. Ricinoleic acid decreases short circuit current in T84 cells, a colonic carcinoma cell line that secretes Cl-. Our results suggest that the direct effect of arachidonic and other fatty acids on Cl- secretion is to block Cl- channel current.

Arachidonic Acid↗
PubMed1989

Acetylcholine and GABA mediate opposing actions on neuronal chloride channels in crayfish.

A central principle of neural integration is that excitatory and inhibitory neurotransmitters effect the opening of distinct classes of membrane ionic channels and that integration consists of the summation of the opposing ionic currents on the postsynaptic membrane. In tangential cells of crayfish optic lobes, a hyperpolarizing, biphasic synaptic potential is produced by the concurrent action of acetylcholine and gamma aminobutyric acid (GABA). Acetylcholine hyperpolarizes the cell and increases chlorine conductance. GABA depolarizes the cell by closing some of the same chloride channels. Therefore, in this case integration is achieved by the antagonistic actions of two transmitters on the same ionic channel.

Acetylcholine↗
PubMed2000

Regulated trafficking of the CFTR chloride channel.

The cystic fibrosis transmembrane conductance regulator (CFTR), the ABC transporter encoded by the cystic fibrosis gene, is localized in the apical membrane of epithelial cells where it functions as a cyclic AMP-regulated chloride channel and as a regulator of other ion channels and transporters. Whereas a key role of cAMP-dependent phosphorylation in CFTR-channel gating has been firmly established, more recent studies have provided clear evidence for the existence of a second level of cAMP regulation, i.e. the exocytotic recruitment of CFFR to the plasma membrane and its endocytotic retrieval. Regulated trafficking of the CFTR Cl- channel has sofar been demonstrated only in a subset of CFTR-expressing cell types. However, with the introduction of more sensitive methods to measure CFTR cycling and submembrane localization, it might turn out to be a more general phenomenon that could contribute importantly to both the regulation of CFTR-mediated chloride transport itself and to the regulation of other transporters and CFTR-modulated cellular functions. This review aims to summarize the present state of knowledge regarding polarized and regulated CFTR trafficking and endosomal recycling in epithelial cells, to discuss present gaps in our understanding of these processes at the cellular and molecular level, and to consider its possible implications for cystic fibrosis.

Animals↗
PubMed1991

The chloride channel blocker 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) uncouples mitochondria and increases the proton permeability of the plasma membrane in phagocytic cells.

We present evidence that the potent chloride channel blocker NPPB has protonophoric activity in the mitochondria and across the plasma membrane of phagocytic cells. The resting O2 consumption of murine peritoneal macrophages was stimulated up to 2.5-fold in the presence of NPPB, with a K0.5 of 15 microM. The stimulatory effect of NPPB on O2 consumption, like that of the classical protonophore CCCP, was prevented by the mitochondrial respiratory chain inhibitors antimycin A, rotenone or cyanide. NPPB also mediated rheogenic proton transport across the plasma membrane of human neutrophils and macrophages in the direction dictated by the electrochemical proton gradient. As a consequence of its protonophoric activity, NPPB uncoupled mitochondrial ATP synthesis, resulting in partial depletion of cellular ATP. These observations indicate that, at the concentrations frequently used for blockade of anion channels, NPPB acts as an effective protonophore, potentially disturbing cytosolic pH and mitochondrial ATP synthesis.

Adenosine Triphosphate↗
PubMed1989

Alpha-chloralose opens the chloride channel of frog isolated sensory neurons.

The effect of alpha-chloralose on the sensory neurons isolated enzymatically and mechanically from frog dorsal root ganglia was studied using a suction-pipette technique. The threshold concentration of alpha-chloralose was around 3 x 10(-5) M and the current produced by alpha-chloralose saturated at the concentration of 3 x 10(-3) M or more. The dose-response curve for alpha-chloralose provided a Ka value of 6 x 10(-4) M and a Hill coefficient of 1.8. The reversal potential of the response elicited by alpha-chloralose was close to the equilibrium potential for Cl- (ECl), indicating that the current was carried through Cl- channels. The current-voltage relationship indicated that there was little voltage dependence in the alpha-chloralose-induced response. The analysis of the variance of the alpha-chloralose-induced Cl- current fluctuations showed two types of the receptor-ionophore complexes with different channel conductances.

Animals↗
PubMed2002

Deficiency in ClC-3 chloride channels prevents rat aortic smooth muscle cell proliferation.

Recent growing evidence suggests that chloride (Cl-) channels are critical to the cell cycle. In cultured rat aortic vascular smooth muscle cells (VSMCs), we have previously found that Cl- channel blockers inhibit endothelin-1 (ET-1)-induced cell proliferation. The present study was designed to further identify the specific Cl- channels responsible for VSMC proliferation. Due to the lack of a specific blocker or opener of any known Cl- channels, we used the antisense strategy to investigate the potential role of ClC-3, a member of the voltage-gated Cl- channel gene family, in cell proliferation of cultured rat aortic VSMCs. With [3H]-thymidine incorporation and immunoblots, we found that ET-1-induced cell proliferation was parallel to a significant increase in the endogenous expression of ClC-3 protein. Transient transfection of rat aortic VSMCs with antisense oligonucleotide specific to ClC-3 caused an inhibition in ET-1-induced expression of ClC-3 protein and cell proliferation of VSMCs in the same concentration- and time-dependent pattern, whereas sense and missense oligonucleotides resulted in no effects on ClC-3 protein expression and cell proliferation. These results strongly suggest that ClC-3 may be the Cl- channel involved in VSMC proliferation and thus provide compelling molecular evidence linking a specific Cl- channel to cell proliferation. The full text of this article is available at http://www.circresaha.org.

Animals↗
PubMed1991

Two types of chloride channels in hen colon epithelial cells identified by patch-clamp experiments.

Freshly isolated epithelial cells from hen colon were investigated using the patch-clamp technique. The aim of this investigation was to characterise the cellular conducting site for Cl- secretion. In cell-attached mode two types of Cl(-)-channels were found. Both showed distinct outward rectification. The channel types differed in single channel conductances and the marked voltage dependence of the open probabilities. A low conductance Cl(-)-channel was observed with a mean conductance at negative holding potentials of g- = 9 pS, and of g+ = 34 pS at positive potentials. This channel was predominantly open at negative potentials, corresponding to cell hyperpolarization. The second channel type observed had conductances of g- = 35 pS and g+ = 77 pS, and showed increasing open probabilities with increasing holding potentials (cell depolarisation). Both channel types were blockable by the Cl(-)-channel blocker NPPB. These data in combination with previously published transepithelial transport data on hen colon indicate that these channels are the Cl- secretory sites in colon epithelium.

Animals↗
PubMed1994

Cell swelling activates separate taurine and chloride channels in Ehrlich mouse ascites tumor cells.

The taurine efflux from Ehrlich ascites tumor cells is stimulated by hypotonic cell swelling. The swelling-activated taurine efflux is unaffected by substitution of gluconate for extracellular Cl- but inhibited by addition of MK196 (anion channel blocker) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS; anion channel and anion exchange blocker) and by depolarization of the cell membrane. This is taken to indicate that taurine does not leave the osmotically swollen Ehrlich cells in exchange for extracellular Cl-, i.e., via the anion exchanger but via a MK196- and DIDS-sensitive channel that is potential dependent. An additional stimulation of the swelling-activated taurine efflux is seen after addition of arachidonic acid and oleic acid. Cell swelling also activates a "Mini Cl- channel." The Cl- efflux via this Cl- channel, in contrast to the swelling-activated taurine efflux, is unaffected by DIDS and inhibited by arachidonic acid and oleic acid. It is suggested that the swelling-activated "Mini Cl- channel" and the swelling-activated taurine channel in the Ehrlich cell represent two distinct types of channels.

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