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PubMed1995

Differential effects of hexachlorocyclohexane isomers on the GABA receptor-chloride channel complex in rat dorsal root ganglion neurons.

The GABAA receptor-chloride channel complex has recently been demonstrated by patch clamp experiments to be the target of cyclodiene insecticides. We have now examined the effects of four isomers of hexachlorocyclohexane (HCH), alpha-, beta-, gamma- and delta-HCH, on the GABAA receptor-chloride channel complex of rat dorsal root ganglion neurons using patch clamp techniques. When co-applied with 10 microM GABA, 1 microM gamma-HCH slightly enhanced and then suppressed the GABA-induced chloride current. The desensitization of the current was greatly accelerated by gamma-HCH in a dose-dependent manner. The acceleration of desensitization and the suppression of sustained component of current by gamma-HCH occurred at lower concentration ranges than those for the suppression of peak current. When 10 microM delta-HCH was co-applied with 10 microM GABA, current was greatly enhanced and then suppressed, and the level of enhancement was much higher than that of gamma-HCH. alpha- and beta-HCH had little or no effect on the GABA-induced chloride current. The differential actions of these isomers on GABA-activated chloride currents account for variable symptoms of poisoning in insects and mammals.

Animals↗
PubMed1991

A chloride channel in rat and human axons.

Current recordings from single chloride channels were obtained from excised and cell-attached patches of rat and human axons. In rat axons the channels showed an outwardly rectifying current-voltage relationship with a slope conductance of 33 pS at negative membrane potentials and 65 pS at positive potentials (symmetrical 150 mM CsCl). They were measurably permeable for cations (PNa/PCs/PCl = 0.1/0.2/1). Channel currents were independent of cytoplasmatic calcium concentration. Inactivation was not observed and gating was weakly voltage dependent. Cl- channels in human axons showed similar gating behavior but had a lower conductance.

Animals↗
PubMed1997

A low conductance chloride channel in the basolateral membranes of the non-pigmented ciliary epithelium of the rabbit eye.

PURPOSE: Chloride efflux plays an important role in aqueous humor production. Chloride currents have been described in bovine non-pigmented ciliary epithelium (NPE), in transformed cultured human NPE, and in bovine volume-activated chloride channels described in the latter. It is the basolateral membranes of the NPE of ocular ciliary processes that comprise the exit pathway for the process of aqueous secretion performed by the double syncytial layer of ciliary epithelium, however. Therefore, we studied both cell-attached, and, excised, inside-out patches from basolateral membranes of the NPE. METHODS: Cell-attached and cell-free excised patches were formed from the basolateral membranes of NPE and single channel currents recorded with a Dagan 3900A patch clamp amplifier. RESULTS: A low conductance channel of 14 pS was observed and recorded in 30% of cell attached patches and in 35% of excised inside out patches under symmetrical conditions (160 mM chloride). This channel displayed a nearly linear current-voltage relationship, with an open probability that was not voltage-dependent. The channel was chloride-selective: N-methyl-D-glucamine (NMDG) used as cation did not alter the current profile nor the reversal protein. Further, with inside-out patches, the reversal potential was close to zero (0.3 +/- 0.5 mV (10) in symmetrical (160 mV) chloride, but shifted to -32.3 +/- 0.5 mV (5) when the concentration of chloride in the bathing solution was reduced to 40 mM while the recording pipette was held at 160 mM. This value approaches the theoretical equilibrium potential of chloride for these conditions. The channel anion permeability sequence was: I- > NO3- > or = Br- > Cl- > gluconate- approximately equal to aspartate-. Three different chloride-channel blockers inhibited the channel activity. CONCLUSION: A low conductance channel, selective for chloride, and, modulated by beta adrenergic and VIP stimulation, based on it sensitivity to exogenously added cAMP, ATP and the catalytic subunit of PKA, is present in the exit basolateral membranes of rabbit NPE and contributes to the process of aqueous humor formation.

Adenosine Triphosphate↗
PubMed2000

Expression, purification, and initial structural characterization of YadQ, a bacterial homolog of mammalian ClC chloride channel proteins.

YadQ of Escherichia coli is a homolog of the mammalian chloride channels of the ClC family. The yadQ gene was cloned as a fusion protein with a hexahistidine tag and tobacco etch virus protease site for the removal of the tag. The protein was expressed in the membrane of E. coli and extracted with decylmaltoside. Purification was achieved by metal affinity chromatography followed by cation exchange. Circular dichroism revealed a high alpha-helical content. Size exclusion chromatography suggests that YadQ forms dimers. The similarity in primary, secondary, and quaternary structure and the ability to recombinantly express YadQ in the cell membrane make the protein a good candidate for the structural study of ClC chloride channels.

Amino Acid Sequence↗
PubMed1999

Perinatal regulation of the ClC-2 chloride channel in lung is mediated by Sp1 and Sp3.

Mechanisms responsible for regulation of pulmonary epithelial chloride-channel expression in the perinatal period are under investigation to better understand normal lung development and airway disease pathogenesis. The ClC-2 epithelial chloride channel is regulated by changes in pH and volume and is most abundant in lung during fetal development. In this study, we identify and sequence the ClC-2 promoter, which is GC rich and lacks a TATA box. By construction of a series of promoter-luciferase constructs, a 67-bp GC box-containing sequence in the promoter is shown to be critical to ClC-2 expression in primary and immortalized fetal lung epithelial cells. Electrophoretic mobility shift assays and antibody supershifts demonstrate that the Sp1 and Sp3 transcription factors are expressed in fetal lung nuclei and interact with the GC box sequences in the promoter. Immunoblotting techniques demonstrate that Sp1 and Sp3 are perinatally downregulated in the lung with the same temporal sequence as ClC-2 downregulation. This work suggests that Sp1 and Sp3 activate ClC-2 gene transcription and that reduction in Sp1 and Sp3 at birth explains perinatal downregulation of ClC-2 in the lung.

Aging↗
PubMed2005

Association between Hsp90 and the ClC-2 chloride channel upregulates channel function.

The voltage-dependent ClC-2 chloride channel has been implicated in a variety of physiological functions, including fluid transport across specific epithelia. ClC-2 is activated by hyperpolarization, weakly acidic external pH, intracellular Cl-, and cell swelling. To add more insight into the mechanisms involved in ClC-2 regulation, we searched for associated proteins that may influence ClC-2 activity. With the use of immunoprecipitation of ClC-2 from human embryonic kidney-293 cells stably expressing the channel, followed by electrophoretic separation of coimmunoprecipitated proteins and mass spectrometry identification, Hsp70 and Hsp90 were unmasked as possible ClC-2 interacting partners. Association of Hsp90 with ClC-2 was confirmed in mouse brain. Inhibition of Hsp90 by two specific inhibitors, geldanamycin or radicicol, did not affect total amounts of ClC-2 but did reduce plasma membrane channel abundance. Functional experiments using the whole cell configuration of the patch-clamp technique showed that inhibition of Hsp90 reduced ClC-2 current amplitude and impaired the intracellular Cl- concentration [Cl-]-dependent rightward shift of the fractional conductance. Geldanamycin and radicicol increased both the slow and fast activation time constants in a chloride-dependent manner. Heat shock treatment had the opposite effect. These results indicate that association of Hsp90 with ClC-2 results in greater channel activity due to increased cell surface channel expression, facilitation of channel opening, and enhanced channel sensitivity to intracellular [Cl-]. This association may have important pathophysiological consequences, enabling increased ClC-2 activity in response to cellular stresses such as elevated temperature, ischemia, or oxidative reagents.

Animals↗
PubMed1994

Aging and chloride channel regulation in rat fast-twitch muscle fibres.

By the use of pharmacological tools, we tested the hypothesis that age-related alterations in the regulatory pathways of chloride channels might contribute to the lowered chloride conductance (GCl) found in skeletal muscle of aged rats. The resting GCl of extensor digitorum longus (EDL) muscles from adult rats either young (3-4 months old) or aged (29 months old) was measured by means of computerized intracellular microelectrode recordings. In EDL muscle from 3 to 4-month-old rats, 4-beta-phorbol 12,13-dibutyrate (4-beta-PDB), a direct activator of protein kinase C (PKC), decreased GCl in a concentration-dependent manner. The same effect was exerted by cholera toxin. The effects of both the phorbol ester and cholera toxin were inhibited by staurosporine, thus indicating that either direct or indirect (via G protein) activation of PKC accounts for the decrease of GCl. An increase of cytosolic Ca2+ by the ionophore A23187 also significantly decreased GCl by 25%. In EDL muscles from aged rats, 4-beta-PDB was 20-fold more potent in blocking GCl than in muscles from younger controls, and the ionophore blocked GCl by 40%. On the other hand, cholera toxin was ineffective. Our findings support the hypothesis that in fast-twitch muscle the regulation of chloride channels by PKC and Ca2+ is a target of the aging process.

Aging↗
PubMed2006

Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.

Chloride channels modulate gastrointestinal neuromuscular functions in vitro. Lubiprostone, a selective type 2 chloride channel (ClC-2) activator, induces intestinal secretion and has been shown to relieve constipation in clinical trials; however, the effects of lubiprostone on gastric function and whole gut transit in humans are unclear. Our aim was to compare the effects of the selective ClC-2 activator lubiprostone on maximum tolerated volume (MTV) of a meal, postprandial symptoms, gastric volumes, and gastrointestinal and colonic transit in humans. We performed a randomized, parallel-group, double-blind, placebo-controlled study evaluating the effects of lubiprostone (24 microg bid) in 30 healthy volunteers. Validated methods were used: scintigraphic gastrointestinal and colonic transit, SPECT to measure gastric volumes, and the nutrient drink ("satiation") test to measure MTV and postprandial symptoms. Lubiprostone accelerated small bowel and colonic transit, increased fasting gastric volume, and retarded gastric emptying. MTV values were reduced compared with placebo; however, the MTV was within the normal range for healthy adults in 13 of 14 participants, and there was no significant change compared with baseline measurements. Lubiprostone had no significant effect on postprandial gastric volume or aggregate symptoms but did decrease fullness 30 min after the fully satiating meal. Thus the ClC-2 activator lubiprostone accelerates small intestinal and colonic transit, which confers potential in the treatment of constipation.

Adolescent↗
PubMed1994

Role of innervation, excitability, and myogenic factors in the expression of the muscular chloride channel ClC-1. A study on normal and myotonic muscle.

The muscular chloride channel (ClC-1) is essential for a normal excitability of mature mammalian muscle fibers; inactivation of the corresponding gene by mutations leads to hyperexcitability of muscle, the hallmark of the disease myotonia. In the mouse, there is very little ClC-1 mRNA in myotubes, and its concentration increases steeply during postnatal development, suggesting a role of the motor nerve in ClC-1 expression. We investigated the response of the expression of the corresponding gene Clc-1 to different patterns of muscle activity as controlled by sarcolemmal excitability and by innervation. In rat and mouse, the level of ClC-1 mRNA was higher in fast (extensor digitorum longus) than in slow (soleus) muscle. Myotonia in the ADR mouse is caused by an insertional mutation leading to the adr allele of the Clc-1 gene and to grossly abnormal ClC-1 mRNAs. Nevertheless, in +/adr heterozygous, phenotypically wild type (WT) animals, the expression levels of both alleles correspond to the gene dosage. However, in the myotonic ADR mouse in which both Clc-1 genes are defective, ClC-1 mRNA levels in slow muscle were nearly as high as in WT fast muscle. In WT muscle, denervation within 2 days caused a drastic reduction of the ClC-1 mRNA level and at the same time an increase of myogenin and MyoD mRNAs. Neither effect of denervation was observed in myotonic mice (homozygous for the alleles adr or adrK), suggesting that spontaneous electrical activity of the hyperexcitable sarcolemma may substitute for nerve activity. Furthermore, potential MyoD/myogenin-binding sequence motifs were identified in the 5' regulatory region of the Clc-1 gene. These findings suggest that the activity-dependent regulation of the muscular chloride channel 1 gene is mediated by myogenic factors.

Amino Acid Sequence↗
PubMed1997

avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.

Ivermectin is a widely used anthelmintic drug whose nematocidal mechanism is incompletely understood. We have used Caenorhabditis elegans as a model system to understand ivermectin's effects. We found that the M3 neurons of the C.elegans pharynx form fast inhibitory glutamatergic neuromuscular synapses. avr-15, a gene that confers ivermectin sensitivity on worms, is necessary postsynaptically for a functional M3 synapse and for the hyperpolarizing effect of glutamate on pharyngeal muscle. avr-15 encodes two alternatively spliced channel subunits that share ligand binding and transmembrane domains and are members of the family of glutamate-gated chloride channel subunits. An avr-15-encoded subunit forms a homomeric channel that is ivermectin-sensitive and glutamate-gated. These results indicate that: (i) an ivermectin-sensitive chloride channel mediates fast inhibitory glutamatergic neuromuscular transmission; and (ii) a nematocidal property of ivermectin derives from its activity as an agonist of glutamate-gated chloride channels in essential excitable cells such as those of the pharynx.

Alternative Splicing↗
PubMed1995

Volume-sensitive chloride channels associated with human cervical carcinogenesis.

Previous controversy has risen from the purported equivalence of the volume-sensitive chloride channels with P-glycoprotein. The aim of this study was to investigate the association between expression of volume-sensitive Cl- channels and the process of malignant transformation of cervical epithelial cells. We studied the activations of volume-sensitive and cAMP-mediated chloride currents in various human cervical squamous cells that were representative of different stages of cervical carcinogenesis, i.e., normal cervical epithelium, low-grade cervical intraepithelial neoplasia, carcinoma in situ, and invasive carcinoma using the whole-cell patch clamp technique. The volume-sensitive chloride channels, however, were significantly activated only in the four cervical cancer cell lines, primary culture cells of carcinoma in situ, and invasive cancer of the cervix. The expression of volume-sensitive chloride currents was independent of the state of human papillomavirus positivity. When these cells were exposed to hypotonic shock, the cells swelled, and outward rectified chloride currents were observed. These effects were readily reversed by returning the cells to isotonic medium. In addition, 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid, 1,9-dideoxyforskolin, and verapamil reversibly abolished the volume-sensitive Cl- currents. In contrast, none of the cells from normal cervices and human papillomavirus-immortalized cell lines, the in vitro equivalent of low-grade cervical intraepithelial neoplasia, developed substantial chloride currents on exposure to hypotonicity. cAMP-mediated chloride currents were ubiquitously activated in all cervical squamous cells, regardless of the stages of carcinogenesis. This is the first report suggesting an in vivo association between the development of volume-sensitive chloride currents and human carcinogenesis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Mercury modulation of GABA-activated chloride channels and non-specific cation channels in rat dorsal root ganglion neurons.

The effects of mercuric chloride and methylmercury chloride on the rat dorsal root ganglion neurons in primary culture were studied by the whole-cell patch clamp technique. gamma-Aminobutyric acid-induced chloride currents were augmented by mercuric chloride in a potent and efficacious manner; at concentrations of 1 and 10 microM, the current amplitude was increased to 130% and 200% of the control. Methylmercury even at 100 microM did not augment but rather decreased the GABA-induced chloride current. Both mercuric chloride and methylmercury generated slow inward currents by themselves. These currents are not mediated by the GABA-activated chloride channels or by voltage-activated sodium, potassium or calcium channels, and are likely to be due to non-specific cation channels.

Animals↗
PubMed1985

Rectification of single GABA-gated chloride channels in adult hippocampal neurons.

The properties of single chloride channels activated by gamma-aminobutyric acid (GABA) were investigated with hippocampal slices from adult guinea pigs. After the slices were treated with proteolytic enzymes, gigaseal recordings were made from excised patches of pyramidal or granule cell membranes. This newly developed preparation permits the application of patch-clamp techniques to the adult mammalian central nervous system. Guinea pig hippocampal slices were prepared in a conventional manner. Once prepared, the slices were treated with two different enzymes for brief periods and gently agitated. Slices generally split apart along the boundaries of the cell body regions, exposing neuronal somata. Standard patch-clamp techniques were used for the gigaseal recordings from excised patches. Solutions for both sides of the patches consisted of symmetrical concentrations of chloride, with all cation channels blocked. GABA at concentrations of 0.5-1.0 microM was added to the solution for the extracellular side of the patches. At transmembrane potentials negative to the chloride reversal potential (0 mV), the conductance through the GABA-gated chloride channels was approximately 20 pS. When the transmembrane potential was changed to positive values, the chloride conductance increased dramatically. For example, at +40 mV the conductance through the GABA-gated channels was almost 40 pS. Ramp-clamp commands were used to measure the current-voltage (I-V) relationship through single open channels. The open-channel I-V curves displayed outward rectification. The relationship between open-channel conductance and voltage could be fitted reasonably well by a single energy-barrier model for the channel, with the higher energy barrier placed near the cytoplasmic side of the membrane (at a fractional distance through the membrane of 0.73).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

ATP-sensitive voltage- and calcium-dependent chloride channels in sarcoplasmic reticulum vesicles from rabbit skeletal muscle.

Chloride channels in the sarcoplasmic reticulum (SR) are thought to play an essential role in excitation-contraction (E-C) coupling by balancing charge movement during calcium release and uptake. In this study the nucleotide-sensitivity of Cl- channels in the SR from rabbit skeletal muscle was investigated using the lipid bilayer technique. Two distinct ATP-sensitive Cl- channels that differ in their conductance and kinetic properties and in the mechanism of ATP-induced channel inhibition were observed. The first, a nonfrequent 150 pS channel was inhibited by trans (luminal) ATP, and the second, a common 75 pS small chloride (SCl) channel was inhibited by cis (cytoplasmic) ATP. In the case of the SCl channel the ATP-induced reversible decline in the values of current (maximal current amplitude, Imax and integral current, I') and kinetic parameters (frequency of opening FO, probability of the channel being open PO, mean open TO and closed Tc times) show a nonspecific block of the voltage- and Ca2+-dependent SCl channel. ATP was a more potent blocker from the cytoplasmic side than from the luminal side of the channel. The SCl channel block was not due to Ca2+ chelation by ATP, nor to phosphorylation of the channel protein. The inhibitory action of ATP was mimicked by the nonhydrolyzable analogue adenylylimidodiphosphate (AMP-PNP) in the absence of Mg2+. The inhibitory potency of the adenine nucleotides was charge dependent in the following order ATP4- > ADP3- > > > AMP2-. The data suggest that ATP-induced effects are mediated via an open channel block mechanism. Modulation of the SCl channel by [ATP]cis and [Ca2+]cis indicates that (i) this channel senses the bioenergetic state of the muscle fiber and (ii) it is linked to the ATP-dependent cycling of the Ca2+ between the SR and the sarcoplasm.

Adenosine Triphosphate↗
PubMed2006

Muscle chloride channel dysfunction in two mouse models of myotonic dystrophy.

Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)(250) repeats (HSA(LR) mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1-3-wk-old wild-type and HSA(LR) mice. The results indicate that peak ClC-1 current density at -140 mV is reduced >70% (-48.5 +/- 3.6 and -14.0 +/- 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18-20- d-old HSA(LR) mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSA(LR) FDB fibers results from a large reduction in ClC-1 channel density (170 +/- 21 and 58 +/- 11 channels/pF in control and HSA(LR) fibers, respectively) and a modest decrease in maximal channel open probability(0.91 +/- 0.01 and 0.75 +/- 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1(DeltaE3/DeltaE3)), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat-containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.

Animals↗
PubMed2001

Sucrase-isomaltase is an adenosine 3',5'-cyclic monophosphate-dependent epithelial chloride channel.

BACKGROUND & AIMS: We previously isolated a monoclonal antibody against a Necturus gallbladder epitope that blocks native adenosine 3',5'-cyclic monophosphate (cAMP)-dependent chloride channels in intestine, gallbladder, urinary bladder, and airway epithelia in various animals. METHODS: Using this antibody, we purified a 200-kilodalton protein that, when reconstituted in lipid bilayers, forms 9-pS chloride channels that are blocked by the antibody. RESULTS: Amino acid sequencing of the purified protein showed strong homology to rabbit sucrase-isomaltase, an abundant intestinal enzyme. Western blot analysis of the in vitro-translated sucrase-isomaltase was indistinguishable from that of the protein used in the lipid bilayer studies. Expression of this protein in Chinese hamster ovary cells and in Xenopus laevis oocytes yielded cAMP-dependent chloride currents that in the latter system were blocked by the antibody. CONCLUSIONS: Because the monoclonal antibody blocks cAMP-dependent currents in epithelia as well as those produced both by the reconstituted and by the heterologously expressed protein, sucrase-isomaltase is a cAMP-dependent epithelial chloride channel. Thus an enzyme that can also function as an ion channel has been described for the first time.

Amino Acid Sequence↗
PubMed2002

Counteraction of the rapid tolerance to 8-hydroxy-2-(di-n-propylamino)tetralin-induced hypothermia in rats by activation of the GABAA receptor-chloride channel complex.

The effects of compounds that open the GABAA receptor-chloride channel complex on the rapidly developed tolerance to the 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide(8-OH-DPAT)-induced hypothermia in rats were examined. The test compound was injected 15 min. before 1 mg/kg subcutaneous 8-OH-DPAT or saline and 24 hr later a challenge dose of 0.1 mg/kg subcutaneous 8-OH-DPAT was given. The rectal temperature was measured before the challenge dose and 30, 60, 90 and 120 min. thereafter. The hypothermic effect was calculated as the area under the curve. It was found that all the GABAergic compounds examined significantly counteracted the 8-OH-DPAT-induced tolerance to the hypothermic response: muscimol at 3 mg/kg subcutaneous, diazepam at 1 - 3 mg/kg subcutaneous, pentobarbitone sodium at 20 mg/kg subcutaneous, and chlormethiazole at 40 mg/kg subcutaneous. Combined treatment of the rats with the GABAA receptor antagonist, bicucculine, or the GABAA receptor-chloride channel blocker, picrotoxin and diazepam, pentoparbitone sodium or chlormethiazole significantly antagonised this counteraction of the 8-OH-DPAT-induced tolerance. Depletion of 5-HT by pretreatment of the rats with the tryptophan hydroxylase inhibitor p-chlorophenylalanine did not counteract the 8-OH-DPAT-induced tolerance to the hypothermic response. Pretreatment of the rats with dexamethazone did not change the development of the tolerance to 8-OH-DPAT-induced hypothermic effect which seems to exclude the involvement of the hypothalamo-pituitary-adrenocortical axis in the tolerance development. It is concluded that the results support the hypothesis that GABA neurones beyond the 5-HT neurones are involved in the mechanism causing tolerance to the 5-HT1A receptor-mediated hypothermia in rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

Genetic differences in coupling of benzodiazepine receptors to chloride channels.

The affinity and density of [3H]flunitrazepam binding sites and the ability of flunitrazepam to augment GABA-activated chloride flux were determined using membrane vesicles prepared from cortex of long-sleep (LS, alcohol-sensitive), short-sleep (SS, alcohol-resistant) and individual heterogeneous stock (HS) mice. LS membranes were more sensitive than SS membranes to the effects of flunitrazepam (and ethanol) on chloride flux but did not differ in the binding of [3H]flunitrazepam. Likewise, individual HS mice displayed marked differences in enhancement of chloride flux by flunitrazepam, but little difference in binding of flunitrazepam. These results suggest that there is little genetic variation in the binding of benzodiazepines to receptors, but there is a marked diversity in the coupling of these receptors to chloride channels. This implies the existence of 'spare receptors' in LS and most HS mice, but not in SS mice. These findings also suggest that genetic differences in alcohol sensitivity in vivo may be related to coupling of benzodiazepine binding to chloride channel function.

Animals↗