共查询到20条相似文献,搜索用时 15 毫秒
1.
Astrocytes are the major glial cells in brain tissue and are involved, among many functions, ionic and metabolic homeostasis maintenance of synapses. These cells express receptors and transporters for neurotransmitters, including GABA. GABA signaling is reportedly able to affect astroglial response to injury, as evaluated by specific astrocyte markers such as glial fibrillary acid protein and the calcium-binding protein, S100B. Herein, we investigated the modulatory effects of the GABAA receptor on astrocyte S100B secretion in acute hippocampal slices and astrocyte cultures, using the agonist, muscimol, and the antagonists pentylenetetrazol (PTZ) and bicuculline. These effects were analyzed in the presence of tetrodotoxin (TTX), fluorocitrate (FLC), cobalt and barium. PTZ positively modify S100B secretion in hippocampal slices and astrocyte cultures; in contrast, bicuculline inhibited S100B secretion only in hippocampal slices. Muscimol, per se, did not change S100B secretion, but prevented the effects of PTZ and bicuculline. Moreover, PTZ-induced S100B secretion was prevented by TTX, FLC, cobalt and barium indicating a complex GABAA communication between astrocytes and neurons. The effects of two putative agonists of GABAA, β-hydroxybutyrate and methylglyoxal, on S100B secretion were also evaluated. In view of the neurotrophic role of extracellular S100B under conditions of injury, our data reinforce the idea that GABAA receptors act directly on astrocytes, and indirectly on neurons, to modulate astroglial response. 相似文献
3.
Abstract: Striatal cholinergic interneurons have been shown to receive input from Striatal γ-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA A and the GABA 6 receptor. Using in vivo microdialysis, we have studied the effect of intrastriatal application of the GABA A-selective compounds muscimol and bicuculline and the GA- BA B-selective compounds baclofen and 2-hydroxysaclofen, agonists and antagonists, respectively, at GABA receptors, on the output of Striatal acetylcholine (ACh). Intrastriatal infusion of 1 and 10 μmol/L concentrations of the GABA A antagonist bicuculline resulted in a significant increase in Striatal ACh output, whereas infusion of 1 and 10 /μmol/L concentrations of the GABA A agonist muscimol significantly decreased the output of Striatal ACh. Both compounds were ineffective in changing the output of Striatal ACh at lower concentrations. Infusion of concentrations up to 100 μmol/L of the GABA B-selective antagonist 2-hydroxy-saclofen failed to affect Striatal ACh output, whereas infusion of 10 and 100 μmol/L baclofen, but not 0.1 and 1 μmol/L baclofen, significantly decreased the output of Striatal ACh. Thus, agonist-stimulation of GABAA and GABA B receptors decreases the output of striatal ACh in a dose-dependent fashion, whereas the GABAergic system appears to inhibit tonically the output of striatal ACh via GABA A receptors, but not via GABA B receptors. We hypothesize that although GABA A mediated regulation of striatal ACh occurs via GABA receptors on the cholinergic neuron, the GABA B mediated effects may be explained by presynaptic inhibition of the glutamatergic input of the striatal cholinergic neuron. 相似文献
4.
Recent evidence has shown in membrane preparations that the binding of one ligand to its receptor is able to modify the binding parameters of a second receptor (receptor-receptor interactions), allowing the modulation of incoming signals onto a neuron. To further understand the -amino-butyric acid (GABA)-dopamine (DA) interactions in the neostriatum we have carried out experiments to explore whether an activation of the GABA A receptor could affect the binding characteristics of the D 2 DA receptor in membrane preparations of the rat neostriatum. The results show that GABA (30–100 nM) significantly increases the dissociation constant of the high affinity (K H) D 2 DA binding site (labelled with the selective D 2 DA receptor antagonist [ 3H]raclopride and that such an effect is fully counteracted by the GABA A receptor antagonist bicuculline (1 M). It is suggested that such putative GABA A/D 2 receptor-receptor interactions may take place in the somato-dendritic membrane of the striato-pallidal GABA neurons and that it may modulate the inhibitory effects of DA on these neurons, mediated via D 2 receptors. 相似文献
5.
The region that becomes the ventromedial nucleus of the hypothalamus (VMH) is surrounded by cells and fibers containing immunoreactive gamma‐aminobutyric acid (GABA) by embryonic day 13 (E13), several days before the nucleus emerges in Nissl stains. As GABA plays many roles during neural development, we hypothesized that it influences VMH development, perhaps by providing boundary information for migrating neurons. To test this hypothesis we examined the VMH in embryonic mice in which the β3 subunit of the GABA A‐receptor, a receptor subunit that is normally highly expressed in this nucleus, was disrupted by gene targeting. In β3 ?/? embryos the VMH was significantly larger, and the distribution of cells containing immunoreactive estrogen receptor‐α was expanded compared to controls. Using in vitro brain slices from wild‐type C57BL/6J mice killed at E15 we found that treatment with the GABA A antagonist bicuculline increased the number of cells migrating per video field analyzed in the VMH. In addition, treatment with either bicuculline or the GABA A agonist muscimol altered the orientation of cell migration in particular regions of this nucleus. These data suggest that GABA is important for the organization of cells during VMH formation. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 264–276, 2001 相似文献
6.
Abstract: P19 embryonic carcinoma (EC) stem cells are pluripotent and are efficiently induced to differentiate into neurons and glia with retinoic acid (RA) treatment. Within 5 days, a substantial number of differentiating P19 cells express gene products that are characteristic of a neuronal phenotype. P19 neurons were used as a model to explore the relationship between neuronal “differentiation” in vitro and the acquisition of γ-aminobutyric acid (GABA A) receptors and functional GABA responses. Pulse-labeling experiments using bromodeoxyuridine indicated that all neurons had become postmitotic within 3–4 days after treatment with RA. This was confirmed by a reduction in the immunocytochemical detection of the undifferentiated stem cell antigen SSEA-1. Subsequently, a transient expression of nestin was observed during the first 5 days in vitro (DIV) after exposure to RA. By 5–10 DIV after RA, a significant number of neurons (~80–90%) expressed immunocytochemically detectable glutamate decarboxylase and GABA coincident with the acquisition of membrane binding sites for tetanus toxin. These phenotypic markers were maintained for >30 DIV after RA. Under current-clamp conditions, random, low-amplitude, spontaneous electrical activity appeared in neurons within the first few days after RA treatment and this was blocked by the specific GABA A receptor antagonist bicuculline. Thereafter, the appearance and progressive increases in the frequency of spontaneous action potentials in P19 neurons were observed that were similarly attenuated by bicuculline. In neurons > 5 DIV after RA, exogenous application of GABA elicited similar action potentials. The onset of excitatory responses to GABA or muscimol in voltage-clamped neurons appeared immediately after the cessation of neuronal mitosis and before the previously reported acquisition of responses to glutamate. In fura-2 imaging studies, the exogenous application of GABA resulted in neuron-specific increases in intracellular Ca 2+. Thus, P19 neurons provide an in vitro model for the study of the early acquisition and properties of electrical excitability to GABA and the expression of functional GABA A receptors. 相似文献
7.
The present study describes the effects of gamma-aminobutyric acid (GABA) and its antagonists, bicuculline and 2-hydroxysaclofen,
on visual responses of neurons in the pigeon nucleus lentiformis mesencephali (nLM). The results indicate that GABA significantly
reduces both spontaneous activity and visual responsiveness, and GABA A antagonist bicuculline but not GABA B antagonist 2-hydroxysaclofen enhances visual responses of nLM cells examined. Furthermore, inhibition produced by motion
in the null-direction of pretectal neurons is diminished by bicuculline but not by 2-hydroxysaclofen. It is therefore concluded
that the null-direction inhibition of directional cells in the pigeon nLM is predominantly mediated by GABA and GABA A receptors. This inhibition may at least in part underlie directional asymmetry of optokinetic responses. 相似文献
8.
The interaction of avermectin B 1a (AVM) with the γ-aminobutyric acid (GABA) receptor of rat brain was studied using radioactive ligand binding and tracer ion flux assays. Avermectin potentiated the binding of [ 3H]flunitrazepam and inhibited the binding of both [ 3H]muscimol and [ 35S] t-butylbicyclo-phosphorothionate to the GABA A receptor. Inhibition of muscimol binding by AVM suggested competitive displacement. Two kinds of 36chloride (Cl) flux were studied. The 36Cl efflux from preloaded microsacs was potentiated by AVM and was highly inhibited by the Cl-channel blocker 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS). However, it was not potentiated by GABA nor was it sensitive to the convulsants picrotoxin or bicuculline. On the other hand, 36Cl-influx measurement in a different microsac preparation of rat brain was very sensitive to GABA and other GABA-ergic drugs. Avermectin induced 36Cl influx into these microsacs in a dose–dependent manner, but to only 35% of the maximal influx induced by GABA. The AVM-induced 36Cl influx was totally blocked by bicuculline. It is suggested that AVM opens the GABA A-receptor Cl channel by binding to the GABA recognition site and acting as a partial receptor agonist, and also opens a voltage–dependent Cl channel which is totally insensitive to GABA but is very sensitive to DIDS. 相似文献
9.
Summary. In order to characterize the possible regulation of taurine release by GABAergic terminals, the effects of several agonists
and antagonists of GABA receptors on the basal and K +-stimulated release of [ 3H]taurine were investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice using a superfusion
system. Taurine release was concentration-dependently potentiated by GABA, which effect was reduced by phaclofen, saclofen
and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at both ages, suggesting regulation by both GABA B and GABA C receptors. The involvement of GABA A receptors could not be excluded since the antagonist bicuculline was able to affect both basal and K +-evoked taurine release. Furthermore, several GABA B receptor effectors were able to inhibit K +-stimulated taurine release in the adults, while the GABA C receptor agonists trans-4-aminocrotonic acid (TACA) and cis-4-aminocrotonic acid (CACA) potentiated this release. The potentiation
of taurine release by agents acting on the three types of GABA receptors in both adult and developing hippocampus further
indicates the involvement of transporters operating in an outward direction. This inference is corroborated by the moderate
but significant inhibition of taurine uptake by the same compounds.
Received June 28, 1999, Accepted August 31, 1999 相似文献
10.
The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABA B receptor agonist; 1–10 μg/5 μl) or bicuculline (a GABA A receptor antagonist; 1–10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABA A receptor agonist; 1–5 μg/5 μl) or phaclofen (a GABA B receptor antagonist; 5–10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen–induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABA B receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABA A receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level. 相似文献
11.
This study was designed to examine the effects of intracerebroventricular (ICV) injection of bicuculline (GABA A receptor antagonist) and muscimol (GABA A receptor agonist) on glutamate-induced eating response in 24-h food-deprived (FD24) broiler cockerels. At first, guide cannula
was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were ICV injected with different
doses of glutamate. In experiment 2, birds were administered with effective dose of glutamate after bicuculline. In experiment
3, chickens received muscimol prior to the injection of glutamate, and cumulative food intake was determined at 3-h postinjection.
The results of this study showed that glutamate decreases food consumption in FD24 broiler cockerels ( P ≤ 0.05), and this reduction occurs in a dose-dependent manner. Moreover, the inhibitory effect of glutamate on food intake
was significantly increased with bicuculline pretreatment, and this effect was attenuated with muscimol ( P ≤ 0.05). These results suggest that there is an interaction between glutamatergic and GABAergic systems (through GABA A receptor) on food intake in broiler cockerels. 相似文献
12.
GABA triggers mammalian sperm acrosome reaction (AR). Here, evidence is presented, showing that rat spermatozoa contain GABA A receptors, composed of 5, 1 and 3 subunits. The effects of GABA A receptor agonist and antagonist on the induction of AR in rat spermatozoa were assessed using the chlortetracycline assay. Muscimol, a GABA A receptor agonist, triggered AR; whereas bicuculline, a GABA A receptor antagonist and picrotoxin, a GABA A receptor/Cl – channel blocker, inhibited the ability of GABA or progesterone to induce AR. In conclusion, GABA A receptors appear to mediate the action of progesterone in inducing AR in rat spermatozoa. 相似文献
13.
Spreading depolarization (SD) is a slowly propagating wave of near complete depolarizations of neurons and glia. Previous studies have reported large GABA releases during SD, but there is limited understanding of how GABA release and receptor activation are regulated and influence the propagating SD wavefront, as well as an excitatory phase immediately following the passage of SD. The present study characterized GABA-A type receptor (GABA AR) currents during SD generated by KCl microinjection in acute hippocampal slices from adult mice. Spontaneous GABA AR-mediated currents (sIPSCs) were initially enhanced, and were followed by a large outward current at the wavefront. sIPSC were then transiently supressed during the late SD phase, resulting in a significant reduction of the sIPSC/sEPSC ratio. The large outward current generated during SD was eliminated by the GABA AR antagonist gabazine, but the channel potentiator/agonist propofol failed to potentiate the current, likely because of a ceiling effect. Extracellular Cl − decreases recorded during SD were reduced by the antagonist but were not increased by the potentiator. Together with effects of GABA AR modulators on SD propagation rate, these results demonstrate a significant inhibitory role of the initial GABA AR activation and suggest that intracellular Cl − loading is insufficient to generate excitatory GABA AR responses during SD propagation. These results provide a mechanistic explanation for facilitating effects of GABA AR antagonists, and the lack of inhibitory effect of GABA AR potentiators on SD propagation. In addition, selective suppression of GABA transmission in the late SD period and the lack of effect of GABA A modulators on the duration of SD suggests that GABA modulation may not be effective approach to protect neurons during the vulnerable phase of SD. 相似文献
14.
Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain in order to study serotonergic-GABAergic interaction. The slices were loaded with either [ 3H] serotonin or [ 3H]GABA, superfused and the electrically induced efflux of radioactivity was determined. The GABA A receptor agonist muscimol (3 to 30 M) and the GABA B receptor agonist baclofen (30 and 100 M) inhibited [ 3H]serotonin and [ 3H]GABA release. These effects of muscimol were reversed by the GABA A antagonists bicuculline (100 M). The GABA B antagonist phaclofen (100 M) also antagonized the baclofen-induced inhibition of [ 3H]serotonin and [ 3H]GABA release. Phaclofen by itself increased [ 3H]serotonin release but it did not alter [ 3H]GABA overflow. Muscimol (10 M) and baclofen (100 M) also inhibited [ 3H]serotonin release after depletion of GABAergic neurons by isoniazid pretreatment. These findings indicate the presence of postsynaptic GABA A and GABA B receptors located on serotonergic neurons. The 5-HT 1A receptor agonist 8-OH-DPAT (0.01 to 1 M) and the 5-HT 1B receptor agonist CGS-12066A (0.01 to 1 M) inhibited the electrically stimulated [ 3H]serotonin and [ 3H]GABA release. The 5-HT 1A antagonist WAY-100135 (1 M) was without effect on [ 3H]serotonin and [ 3H]GABA efflux by itself but it reversed the 8-OH-DPAT-induced transmitter release inhibition. During KCl (22 mM)-induced depolarization, tetrodotoxin (1 M) did not alter the inhibitory effect of CGS-12066A (1 M) on [ 3H]GABA release, it did blocked, however, the ability of 8-OH-DPAT (1 M) to reduce [ 3H]GABA efflux. After depletion of raphe serotonin neurons by p-chlorophenylalanine pretreatment, CGS-12066A (1 M) still inhibited [ 3H]GABA release whereas in serotonin-depleted slices, 8-OH-DPAT (1 M) was without effect on the release. We conclude that reciprocal influence exists between serotonergic projection neurons and the GABAergic interneurons or afferents in the raphe nuclei and these interactions may be mediated by 5-HT 1A/B and GABA A/B receptors. Both synaptic and non-synaptic neurotransmission may be operative in the 5-HTergic-GABAergic reciprocal interaction which may serve as a local tuning in the neural connection between cerebral cortex and midbrain raphe nuclei. 相似文献
15.
A developmental “switch” in chloride transporters occurs in most neurons resulting in GABA A mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABA A receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABA A receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABA A receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABA A activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABA A mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABA A receptor activation in NKCC1 -/- mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1 -/- mice retained relatively normal responses to the GABA A agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO 3
- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABA A mediated transmission in GnRH neurons. 相似文献
16.
The neurotransmitter gamma-aminobutyric acid (GABA) and subtypes of GABA receptors were recently identified in adult testes. Since adult Leydig cells possess both the GABA biosynthetic enzyme glutamate decarboxylase (GAD), as well as GABA A and GABA B receptors, it is possible that GABA may act as auto-/paracrine molecule to regulate Leydig cell function. The present study was aimed to examine effects of GABA, which may include trophic action. This assumption is based on reports pinpointing GABA as regulator of proliferation and differentiation of developing neurons via GABA A receptors. Assuming such a role for the developing testis, we studied whether GABA synthesis and GABA receptors are already present in the postnatal testis, where fetal Leydig cells and, to a much greater extend, cells of the adult Leydig cell lineage proliferate. Immunohistochemistry, RT-PCR, Western blotting and a radioactive enzymatic GAD assay evidenced that fetal Leydig cells of five-six days old rats possess active GAD protein, and that both fetal Leydig cells and cells of the adult Leydig cell lineage possess GABA A receptor subunits. TM3 cells, a proliferating mouse Leydig cell line, which we showed to possess GABA A receptor subunits by RT-PCR, served to study effects of GABA on proliferation. Using a colorimetric proliferation assay and Western Blotting for proliferating cell nuclear antigen (PCNA) we demonstrated that GABA or the GABA A agonist isoguvacine significantly increased TM3 cell number and PCNA content in TM3 cells. These effects were blocked by the GABA A antagonist bicuculline, implying a role for GABA A receptors. In conclusion, GABA increases proliferation of TM3 Leydig cells via GABA A receptor activation and proliferating Leydig cells in the postnatal rodent testis bear a GABAergic system. Thus testicular GABA may play an as yet unrecognized role in the development of Leydig cells during the differentiation of the testicular interstitial compartment. 相似文献
17.
GABA receptor binding to mammalian neuronal membranes has been classified into at least 2 subtypes—GABA A and GABA B binding sites. In catfish brain GABA A receptor sites have previously been demonstrated. Evidence is now presented that under appropriate conditions which rule out GABA A receptor binding, [ 3H]GABA binds to membranes prepared from catfish brain. This binding is bicuculline-insensitive but differs enough from mammalian GABA B binding to cast some doubt on the idea that GABA B receptors exist in catfish brain. Specific binding was detected that was saturable and exhibited a dissociation constant of 4μM. (±)Baclofen, a potent inhibitor in rat brain, was a weak inhibitor, producing a maximum of 43% inhibition. This inhibitory effect could be enhanced, however, in the presence of 320 μM isoguvacine. [ 3H]GABA binding was unaffected by bicuculline. Thus bicuculline-insensitive GABA binding sites exist in catfish brain but they differ in a number of ways from the GABA B receptor site found in mammals. Furthermore, a third [ 3H]GABA binding site appears to exist that is both baclofen- and bicuculline-insensitive, yet is inhibited by high concentrations of isoguvacine, a known GABA A agonist. 相似文献
18.
Motor neurones of the crayfish walking system display inhibitory responses evoked either by γ-amino butyric acid (GABA) or
glutamate, possibly involving the same receptor (Pearlstein et al. 1994). In order to test if this sensibility to both GABA
and glutamate was a specific property of crayfish GABA receptors, pharmacological characteristics of GABA-evoked responses
in both sensory terminals from CB chordotonal organ and motor neurones of the walking system have been compared. Both receptors
are GABA-gated Cl − channels activated by specific GABA A (muscimol, isoguvacine), GABA B (3-aminopropyl phosphinic acid), and GABA C ( cis-4-amino crotonic acid) agonists, and blocked by competitive (β-guanidino propionic acid) and non-competitive (picrotoxin)
antagonists. They were insensitive to specific GABA A (bicuculline, SR-95531) and GABA B (phaclofen) antagonists. Furthermore, in both cases, nipecotic acid and the modulatory drug diazepam had no effect. However,
our results demonstrate that GABA receptors of sensory terminals are different from those of motor neurones. GABA-induced
desensitisation only occurred in sensory terminals. Moreover, glutamate was shown to activate GABA-gated Cl − channels in motor neurones, but not in sensory terminals. Therefore, GABA is likely to be the endogenous neurotransmitter
of presynaptic inhibition in sensory terminals, whereas inhibition between antagonistic motor neurones would be achieved by
glutamate.
Accepted: 10 July 1996 相似文献
19.
This paper reports the functional expression and pharmacological characterization of a full length complementary deoxyribonucleic
acid (cDNA) (pIVY12) cloned from a Heliothis virescens fertilized egg cDNA library that encodes for a γ-aminobutyric acid (GABA) receptor subunit (HVRDL-Ser 285). Two electrode
voltage clamp recordings of Xenopus oocytes expressing the HVRDL GABA-gated chloride channel revealed robust chloride ion conductance in response to GABA and
the GABA A receptor agonist, muscimol. Baclofen, a GABA B agonist had no effect. Phenobarbital showed a positive dose-dependent allosteric modulatory effect, whereas the benzodiazepine,
flunitrazepam, had no effect. Chloride conductance was depressed by the novel insecticide, fipronil ((±)-5-amino-1-(2,6 dichloro-α,
α, α-trifluoro-p-tolyl)-4-trifluoromethyl-sulfinylpyrazole-3-carbonitrile) and the GABA A antagonist, picrotoxinin. The HVRDL GABA receptor was insensitive to blockage by dieldrin and the GABA A antagonist, bicuculline. The comparative actions of fipronil, picrotoxinin and dieldrin were examined on oocytes expressing
the H. virescens wild-type (HVRDL-Ser 285), the site-directed mutant (HVRDL-Ala 285), the Drosophila melanogaster Rdl wild-type (DMRDL-Ala 302) and the Rdl dieldrin resistant (DMRDL-Ser 302) homo-oligomeric GABA receptors. HVRDL-Ala 285 was 15-fold more sensitive to blockage by
fipronil than HVRDL-Ser 285. DMRDL-Ala 302 and DMRDL-Ser-302 showed a similar level of sensitivity to blockage by fipronil.
HVRDL-Ser 285 and DMRDL-Ser 302 exhibited a similar level of insensitivity to picrotoxinin. HVRDL-Ala 285 and DMRDL-Ala 302
showed a similar range of picrotoxinin sensitivity. DMRDL-Ala 302 and HVRDL-Ala 285 showed some sensitivity to blockage by
dieldrin. Fipronil sensitivity was significantly altered by the serine to alanine mutation at position 285 in the M2 region
of the HVRDL subunit, whereas no difference was observed between the DMRDL-Ser 302 and DMRDL-Ala 302 receptors. 相似文献
20.
GABA is the key inhibitory neurotransmitter in the adult central nervous system, but in some circumstances can lead to a paradoxical excitation that has been causally implicated in diverse pathologies from endocrine stress responses to diseases of excitability including neuropathic pain and temporal lobe epilepsy. We undertook a computational modeling approach to determine plausible ionic mechanisms of GABA A-dependent excitation in isolated post-synaptic CA1 hippocampal neurons because it may constitute a trigger for pathological synchronous epileptiform discharge. In particular, the interplay intracellular chloride accumulation via the GABA A receptor and extracellular potassium accumulation via the K/Cl co-transporter KCC2 in promoting GABA A-mediated excitation is complex. Experimentally it is difficult to determine the ionic mechanisms of depolarizing current since potassium transients are challenging to isolate pharmacologically and much GABA signaling occurs in small, difficult to measure, dendritic compartments. To address this problem and determine plausible ionic mechanisms of GABA A-mediated excitation, we built a detailed biophysically realistic model of the CA1 pyramidal neuron that includes processes critical for ion homeostasis. Our results suggest that in dendritic compartments, but not in the somatic compartments, chloride buildup is sufficient to cause dramatic depolarization of the GABA A reversal potential and dominating bicarbonate currents that provide a substantial current source to drive whole-cell depolarization. The model simulations predict that extracellular K + transients can augment GABA A-mediated excitation, but not cause it. Our model also suggests the potential for GABA A-mediated excitation to promote network synchrony depending on interneuron synapse location - excitatory positive-feedback can occur when interneurons synapse onto distal dendritic compartments, while interneurons projecting to the perisomatic region will cause inhibition. 相似文献
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