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1
Feigenspan, Andreas, and Reto Weiler. "Electrophysiological Properties of Mouse Horizontal Cell GABAA Receptors." Journal of Neurophysiology 92, no. 5 (November 2004): 2789–801. http://dx.doi.org/10.1152/jn.00284.2004.
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GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 μM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 μM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 μM in a noncompetitive manner. Furthermore, GABA receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-β-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%.
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Laroute, Valérie, Roberto Mazzoli, Pascal Loubière, Enrica Pessione, and Muriel Cocaign-Bousquet. "Environmental Conditions Affecting GABA Production in Lactococcus lactis NCDO 2118." Microorganisms 9, no. 1 (January 7, 2021): 122. http://dx.doi.org/10.3390/microorganisms9010122.
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GABA (γ-aminobutyric acid) production has been widely described as an adaptive response to abiotic stress, allowing bacteria to survive in harsh environments. This work aimed to clarify and understand the relationship between GABA production and bacterial growth conditions, with particular reference to osmolarity. For this purpose, Lactococcus lactis NCDO 2118, a GABA-producing strain, was grown in glucose-supplemented chemically defined medium containing 34 mM L-glutamic acid, and different concentrations of salts (chloride, sulfate or phosphate ions) or polyols (sorbitol, glycerol). Unexpectedly, our data demonstrated that GABA production was not directly related to osmolarity. Chloride ions were the most significant factor influencing GABA yield in response to acidic stress while sulfate ions did not enhance GABA production. We demonstrated that the addition of chloride ions increased the glutamic acid decarboxylase (GAD) synthesis and the expression of the gadBC genes. Finally, under fed-batch conditions in a complex medium supplemented with 0.3 M NaCl and after a pH shift to 4.6, L. lactis NCDO 2118 was able to produce up to 413 mM GABA from 441 mM L-glutamic acid after only 56 h of culture, revealing the potential of L. lactis strains for intensive production of this bioactive molecule.
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Sallard, Erwan, Diane Letourneur, and Pascal Legendre. "Electrophysiology of ionotropic GABA receptors." Cellular and Molecular Life Sciences 78, no. 13 (June 1, 2021): 5341–70. http://dx.doi.org/10.1007/s00018-021-03846-2.
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AbstractGABAA receptors are ligand-gated chloride channels and ionotropic receptors of GABA, the main inhibitory neurotransmitter in vertebrates. In this review, we discuss the major and diverse roles GABAA receptors play in the regulation of neuronal communication and the functioning of the brain. GABAA receptors have complex electrophysiological properties that enable them to mediate different types of currents such as phasic and tonic inhibitory currents. Their activity is finely regulated by membrane voltage, phosphorylation and several ions. GABAA receptors are pentameric and are assembled from a diverse set of subunits. They are subdivided into numerous subtypes, which differ widely in expression patterns, distribution and electrical activity. Substantial variations in macroscopic neural behavior can emerge from minor differences in structure and molecular activity between subtypes. Therefore, the diversity of GABAA receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types.
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Blanton, M. G., and A. R. Kriegstein. "Properties of amino acid neurotransmitter receptors of embryonic cortical neurons when activated by exogenous and endogenous agonists." Journal of Neurophysiology 67, no. 5 (May 1, 1992): 1185–200. http://dx.doi.org/10.1152/jn.1992.67.5.1185.
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1. The properties of receptors for amino acid neurotransmitters expressed by developing cortical neurons were studied with the use of whole-cell recording in the intact cerebral cortex of embryonic turtles in vitro. The inhibitory agonist gamma-aminobutyric acid (GABA) and the excitatory agonist glutamate were focally applied to single cells under voltage clamp, and the ionic dependence, voltage dependence, and pharmacological sensitivity of the responses were characterized. The responses mediated by a glutamate receptor subtype, the N-methyl-D-aspartate (NMDA) receptor, produced by glutamate and by evoked release of an endogenous excitatory agonist, were compared further. Fluctuation analysis was used to characterize the properties of the NMDA channels and the mechanism of action of receptor antagonists. 2. When postmitotic neurons first appeared at stage 15, all neurons tested responded to GABA with a current that reversed at the equilibrium potential for chloride ions and that was sensitive to the GABAA receptor antagonist bicuculline methiodide (BMI). As development proceeded, an increasing proportion of neurons also responded with a BMI-insensitive current that reversed near the equilibrium potential for potassium ions. This current was blocked by the GABAB receptor antagonist 3-amino-2-propyl phosponic acid (phaclofen). The GABAB agonist baclofen, however, failed to produce a detectable postsynaptic current. 3. Neurons at stage 15 showed a biphasic response to glutamate that reversed at the equilibrium potential for cations. All neurons tested showed a slow, sustained response associated with an increase in current variance compared with background, and, as development proceeded, an increasing proportion also exhibited a fast, transient response. Both fast and slow responses varied linearly with voltage in the absence of Mg2+ ions, but the addition of Mg2+ ions to the bathing medium attenuated the slow response at hyperpolarized potentials. As a result, the current-voltage relation of the slow response in the presence of Mg2+ ions exhibited a region of negative slope conductance, like that of currents mediated by NMDA receptors. 4. The fast and slow responses to glutamate differed in their pharmacological sensitivity. The fast responses were sensitive to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), whereas the slow responses were sensitive to the NMDA receptor antagonist D(-)-2-amino-5-phosphonovalerate (D-APV). 5. When cells were held at -70 mV, glutamate evoked a fluctuating current consisting of channel currents with a mean open time, tau, of 4.42 +/- 0.47 (SE) ms in early postmitotic neurons at stage 15 and 4.99 +/- 0.38 ms at stages 17-20.(ABSTRACT TRUNCATED AT 400 WORDS)
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Feigenspan, Andreas, Stefano Gustincich, and Elio Raviola. "Pharmacology of GABAA Receptors of Retinal Dopaminergic Neurons." Journal of Neurophysiology 84, no. 4 (October 1, 2000): 1697–707. http://dx.doi.org/10.1152/jn.2000.84.4.1697.
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When the vertebrate retina is stimulated by light, a class of amacrine or interplexiform cells release dopamine, a modulator responsible for neural adaptation to light. In the intact retina, dopamine release can be pharmacologically manipulated with agonists and antagonists at GABAA receptors, and dopaminergic (DA) cells receive input from GABAergic amacrines. Because there are only 450 DA cells in each mouse retina and they cannot be distinguished in the living state from other cells on the basis of their morphology, we used transgenic technology to label DA cells with human placental alkaline phosphatase, an enzyme that resides on the outer surface of the cell membrane. We could therefore identify DA cells in vitro after dissociation of the retina and investigate their activity with whole cell voltage clamp. We describe here the pharmacological properties of the GABAA receptors of solitary DA cells. GABA application induces a large inward current carried by chloride ions. The receptors are of the GABAA type because the GABA-evoked current is blocked by bicuculline. Their affinity for GABA is very high with an EC50 value of 7.4 μM. Co-application of benzodiazepine receptor ligands causes a strong increase in the peak current induced by GABA (maximal enhancement: CL-218872 220%; flunitrazepam 214%; zolpidem 348%) proving that DA cells express a type I benzodiazepine-receptor (BZ1). GABA-evoked currents are inhibited by Zn2+ with an IC50 of 58.9 ± 8.9 μM. Furthermore, these receptors are strongly potentiated by the modulator alphaxalone with an EC50 of 340 ± 4 nM. The allosteric modulator loreclezole increases GABA receptor currents by 43% (1 μM) and by 107% (10 μM). Using outside-out patches, we measured in single-channel recordings a main conductance (29 pS) and two subconductance (20 and 9 pS) states. We have previously shown by single-cell RT-PCR and immunocytochemistry that DA cells express seven different GABAA receptor subunits (α1, α3, α4, β1, β3, γ1, γ2S, and γ2L) and by immunocytochemistry that all subunits are expressed in the intact retina. We show here that at least α1, β3 and γ2 subunits are assembled into functional receptors.
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Rudolph, Uwe. "Identification of Molecular Substrate for the Attenuation of Anxiety: A Step Toward the Development of Better Anti-Anxiety Drugs." Scientific World JOURNAL 1 (2001): 192–93. http://dx.doi.org/10.1100/tsw.2001.33.
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Anxiety disorders affect some 19 million people in the U.S. alone, costing $46.6 billion, or one third of the nation’s total mental health bill in 1990. Benzodiazepine tranquilizers like the prototypic diazepam are among the most widely used anti-anxiety agents. In addition to their anxiolytic action, they also induce sedation and may impair motor coordination, both of which are undesired side effects when they are used as anxiolytics. Not surprisingly, road traffic accidents may be increased for patients on classical benzodiazepines. In addition, these drugs carry the risk of dependence liability. Benzodiazepines augment the action of the inhibitory neurotransmitter g-aminobutyric acid (GABA) at contact points between two nerve cells called synapses, points at which information is transmitted from one nerve cell to the next. Synaptically released GABA binds to postsynaptic GABAA receptors, thus causing an influx of negatively charged chloride ions into the postsynaptic neuron. This leads to a hyperpolarization and thus functional inhibition of the postsynaptic cell. Benzodiazepines bind to a site on the GABAAreceptor which is different from the GABA binding site, thus increasing the chloride current. Benzodiazepines like diazepam bind to GABAAreceptors containing the α subunits α1, α2, α3, or α5, most likely in abgabg combinations.
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Blaxter, Timothy J., and Peter L. Carlen. "GABA responses in rat dentate granule neurons are mediated by chloride." Canadian Journal of Physiology and Pharmacology 66, no. 5 (May 1, 1988): 637–42. http://dx.doi.org/10.1139/y88-099.
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The dendrites of granule cells in hippocampal slices responded to γ-aminobutyric acid (GABA) with a depolarization. The response was blocked by picrotoxin in a noncompetitive manner. Reductions in the extracellular chloride ion concentration changed the reversal potential of the response by an amount predicted from the Nernst equation for chloride ion. Chloride-dependent hyperpolarizing responses were sometimes also found in the cell body of the granule cells. Since the reversal potential followed that predicted from the Nernst equation for chloride, we conclude that the response was mediated by chloride ions alone with no contribution from other ions. This has not previously been shown for the depolarizing response to GABA in central neurons.
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Hilgemann, Donald W., and Chin-Chih Lu. "Gat1 (Gaba:Na+:Cl−) Cotransport Function." Journal of General Physiology 114, no. 3 (September 1, 1999): 459–76. http://dx.doi.org/10.1085/jgp.114.3.459.
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We have developed an alternating access transport model that accounts well for GAT1 (GABA:Na+:Cl−) cotransport function in Xenopus oocyte membranes. To do so, many alternative models were fitted to a database on GAT1 function, and discrepancies were analyzed. The model assumes that GAT1 exists predominantly in two states, Ein and Eout. In the Ein state, one chloride and two sodium ions can bind sequentially from the cytoplasmic side. In the Eout state, one sodium ion is occluded within the transporter, and one chloride, one sodium, and one γ-aminobutyric acid (GABA) molecule can bind from the extracellular side. When Ein sites are empty, a transition to the Eout state opens binding sites to the outside and occludes one extracellular sodium ion. This conformational change is the major electrogenic GAT1 reaction, and it rate-limits forward transport (i.e., GABA uptake) at 0 mV. From the Eout state, one GABA can be translocated with one sodium ion to the cytoplasmic side, thereby forming the *Ein state. Thereafter, an extracellular chloride ion can be translocated and the occluded sodium ion released to the cytoplasm, which returns the transporter to the Ein state. GABA–GABA exchange can occur in the absence of extracellular chloride, but a chloride ion must be transported to complete a forward transport cycle. In the reverse transport cycle, one cytoplasmic chloride ion binds first to the Ein state, followed by two sodium ions. One chloride ion and one sodium ion are occluded together, and thereafter the second sodium ion and GABA are occluded and translocated. The weak voltage dependence of these reactions determines the slopes of outward current–voltage relations. Experimental results that are simulated accurately include (a) all current–voltage relations, (b) all substrate dependencies described to date, (c) cis–cis and cis–trans substrate interactions, (d) charge movements in the absence of transport current, (e) dependencies of charge movement kinetics on substrate concentrations, (f) pre–steady state current transients in the presence of substrates, (g) substrate-induced capacitance changes, (h) GABA–GABA exchange, and (i) the existence of inward transport current and GABA–GABA exchange in the nominal absence of extracellular chloride.
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Katchman, A. N., S. Vicini, and N. Hershkowitz. "Mechanism of early anoxia-induced suppression of the GABAA-mediated inhibitory postsynaptic current." Journal of Neurophysiology 71, no. 3 (March 1, 1994): 1128–38. http://dx.doi.org/10.1152/jn.1994.71.3.1128.
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1. We investigated the mechanism of hypoxia-induced depression of gamma-aminobutyric acid-A (GABAA)-mediated inhibitory postsynaptic currents (IPSCs) in CA1 neurons of hippocampal slices from 21- to 28-day-old rats. Cells were examined by whole-cell patch-clamp recording and hypoxia was induced by switching perfusion of the slice from oxygenated artificial cerebral spinal fluid (ACSF) to ACSF saturated with 95% N2-5% CO2. 2. Synaptic responses evoked by stimulation of the Schaffer collateral-commissural projection at a fixed holding potential (VH = -60 mV) during anoxia revealed that the IPSC appeared more sensitive than the excitatory postsynaptic current to anoxia-induced depression. All subsequent studies examined the GABAA-mediated IPSC synaptic responses in isolation by direct stimulation of GABA interneurons in the stratum radiatum in the presence of extracellular 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP) (20 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (50 microM) to block glutamatergic currents and intracellular QX-314 (lidocaine N-ethyl bromide, 1 mM) to block GABAB-mediated currents. When studied in this manner (VH = -60 mV) the GABAA-mediated IPSC appeared to change from an outward to inward current after exposure to anoxia. 3. The current-voltage relationship of GABAA-mediated IPSCs revealed that these changes resulted from a positive shift in the IPSC reversal potential without a significant change in the conductance. Thus under patch clamp apparent IPSC inhibition may result from a decrease in the extracellular concentration of chloride ions. Similar findings were observed with micropipettes that contained high intracellular chloride concentrations. 4. Miniature spontaneous IPSCs were examined in the presence of tetrodotoxin (1 microM) with micropipettes containing high intracellular chloride concentrations. The miniature IPSCs (mIPSCs) appeared as spontaneous transient inward currents. Consistent with an anoxia-induced decrease in extracellular chloride, the mean amplitude of the mIPSCs increased after the onset of anoxia. A significant decrease in rise and decay time was also noted during anoxia. The frequency of the mIPSCs also increased by approximately 300%. 5. The resting input resistance of the cells was examined by measuring the current resulting from a 20-mV hyperpolarizing pulse. A significant reduction in resistance was observed 2 min after the onset of anoxia. This still occurred, although to a lesser degree, in the presence of glutamatergic blockers (20 microM CPP plus 50 microM CNQX). In the presence of both GABAergic (picrotoxin, 100 microM) and glutamatergic blockers no significant reduction in resting input resistance was apparent after 2 min of anoxia.(ABSTRACT TRUNCATED AT 400 WORDS)
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Poisbeau, P. "Pharmacologie des anxiolytiques." European Psychiatry 30, S2 (November 2015): S8. http://dx.doi.org/10.1016/j.eurpsy.2015.09.032.
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La cible principale des anxiolytiques est le récepteur-canal GABAA. Constitué de 5 sous-unités protéiques (majoritairement 2 alpha, 2 bêta, 1 gamma dans le système nerveux), il devient perméable aux ions chlorures après fixation d’au moins deux molécules d’acide gamma-aminobutyrique (GABA). Certains anxiolytiques, comme les benzodiazépines ou l’étifoxine, sont des modulateurs allostériques : ils augmentent cette perméabilité et renforcent ainsi l’inhibition des neurones qui expriment le récepteur GABAA. Le site de liaison des benzodiazépines est bien connu. À distance du site agoniste pour le GABA, il se situe à l’interface entre les sous-unités alpha gamma du récepteur. Notons que le zolpidem, une molécule non benzodiazépinique, se fixe également sur ce site avec une très haute affinité. Dans la classe des anxiolytiques, le chlorhydrate d’étifoxine (laboratoire Biocodex, Gentilly, France) occupe une place intéressante. L’étifoxine n’est pas une benzodiazépine et se fixe sur les sous-unités bêta du récepteur (bêta 2 > bêta 3). Ceci pourrait expliquer pourquoi son activité anxiolytique n’est pas associée à des manifestations indésirables comme la sédation, les troubles mnésiques et la tolérance fonctionnelle. Ainsi, lors de l’arrêt des traitements aucune pharmacodépendance n’est observée. L’étifoxine exerce également une action originale sur la mitochondrie en renforçant les systèmes cellulaires de neuroprotection et en favorisant la production d’un anxiolytique endogène, l’alloprégnanolone. L’alloprégnanolone est à ce jour le plus puissant stimulateur endogène connu de la fonction inhibitrice du récepteur GABAA. Nos travaux récents chez l’animal montrent les effets de cette double action sur les troubles anxieux et dépressif induits par la douleur neuropathique. Ils mettent également en évidence l’intérêt de la molécule pour soulager les symptômes douloureux périphériques dans de nombreux modèles de douleurs.
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Hartveit, E. "Membrane currents evoked by ionotropic glutamate receptor agonists in rod bipolar cells in the rat retinal slice preparation." Journal of Neurophysiology 76, no. 1 (July 1, 1996): 401–22. http://dx.doi.org/10.1152/jn.1996.76.1.401.
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1. With the use of the whole cell voltage-clamp technique, I have recorded the current responses to ionotropic glutamate receptor agonists of rod bipolar cells in vertical slices of rat retina. Rod bipolar cells constitute a single population of cells and were visualized by infrared differential interference contrast video microscopy. They were targeted by the position of their cell bodies in the inner nuclear layer and, after recording, were visualized in their entirety by labeling with the fluorescent dye Lucifer yellow, which was included in the recording pipette. To study current-voltage relationships of evoked currents, voltage-gated potassium currents were blocked by including Cs+ and tetraethylammonium+ in the recording pipette. 2. Pressure application of the non-N-methyl-D-aspartate (non-NMDA) receptor agonists kainate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) from puffer pipettes evoked a long-latency conductance increase selective for chloride ions. When the intracellular chloride concentration was increased, the reversal potential changed, corresponding to the change in equilibrium potential for chloride. The response was evoked in the presence of 5 mM Co2+ and nominally O mM Ca2+ in the extracellular solution, presumably blocking all external Ca2(+)-dependent release of neurotransmitter. 3. The long latency of kainate-evoked currents in bipolar cells contrasted with the short-latency currents evoked by gamma-aminobutyric acid (GABA) and glycine in rod bipolar cells and by kainate in amacrine cells. 4. Application of NMDA evoked no response in rod bipolar cells. 5. Coapplication of AMPA with cyclothiazide, a blocker of agonist-evoked desensitization of AMPA receptors, enhanced the conductance increase compared with application of AMPA alone. Coapplication of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione blocked the response to kainate and AMPA, indicating that the response was mediated by conventional ionotropic glutamate receptors. 6. The conductance increase evoked by non-NMDA receptor agonists could not be blocked by a combination of 100 microM picrotoxin and 10 microM strychnine. Application of the GABAC receptor antagonist 3-aminopropyl (methyl)phosphinic acid (3-APMPA) strongly reduced the response, and coapplication of 500 microM 3-APMPA and 100 microM picrotoxin completely blocked the response. These results suggested that the conductance increase evoked by non-NMDA receptor agonists was mediated by release of GABA and activation of GABAC receptors, and most likely also GABAA receptors, on rod bipolar cells. 7. Kainate responses like those described above could not be evoked in bipolar cells in which the axon had been cut somewhere along its passage to the inner plexiform layer during the slicing procedure. This suggests that the response was dependent on the integrity of the axon terminal in the inner plexiform layer, known to receive GABAergic synaptic input from amacrine cells. 8. The results indicate that ionotropic glutamate receptors are not involved in mediating synaptic input from photoreceptors to rod bipolar cells and that an unconventional mechanism of GABA release from amacrine cells might operate in the inner plexiform layer.
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Bertram, Simone, Francesca Cherubino, Elena Bossi, Michela Castagna, and Antonio Peres. "GABA reverse transport by the neuronal cotransporter GAT1: influence of internal chloride depletion." American Journal of Physiology-Cell Physiology 301, no. 5 (November 2011): C1064—C1073. http://dx.doi.org/10.1152/ajpcell.00120.2011.
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The role of intracellular ions on the reverse GABA transport by the neuronal transporter GAT1 was studied using voltage-clamp and [3H]GABA efflux determinations in Xenopus oocytes transfected with heterologous mRNA. Reverse transport was induced by intracellular GABA injections and measured in terms of the net outward current generated by the transporter. Changes in various intracellular ionic conditions affected the reverse current: higher concentrations of Na+ enhanced the ratio of outward over inward transport current, while a considerable decrease of the outward current and a parallel reduction of the transporter-mediated GABA efflux were observed after treatments causing a diminution of the intracellular Cl− concentration. Particularly interesting was the impairment of the reverse transport observed after depletion of internal Cl− generated by the activity of a coexpressed K+-Cl− exporter KCC2. This finding suggests that reverse GABA transport may be physiologically regulated during early neuronal development, similarly to the functional alterations seen in GABA receptors caused by KCC2 activity.
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Ishibashi, Masaru, Kiyoshi Egawa, and Atsuo Fukuda. "Diverse Actions of Astrocytes in GABAergic Signaling." International Journal of Molecular Sciences 20, no. 12 (June 18, 2019): 2964. http://dx.doi.org/10.3390/ijms20122964.
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An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the “tripartite” synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.
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Khanal, Shyam P., Rajendra P. Koirala, Esha Mishra, and Narayan Prasad Adhikari. "Molecular dynamics study of structural properties of γ-aminobutyric acid (GABA)." BIBECHANA 18, no. 1 (January 1, 2021): 67–74. http://dx.doi.org/10.3126/bibechana.v18i1.29442.
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The study of structural conformation of Gamma-aminobutyric acid (GABA) exhibits its biological and chemical activities. The GABA molecule is responsible in neurotransmission from one neuron to another neuron and activates the ion channels to pass the chlorine and sodium ions in nerve cells. Its conformation in solid state and gas state are extremely different and it also shows five different conformations in aqueous solution. The study of its structure in such environment can reveal its activity in cellular environment. We have performed the classical molecular dynamics study of this system of GABA in aqueous medium to deal its structure. Radial distribution function (RDF) has been used to study the structural properties of the system.
BIBECHANA 18 (2021) 67-74
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MENZIKOV, SERGEY A. "NEURONAL MULTIFUNCTIONAL ATPase." Biophysical Reviews and Letters 08, no. 03n04 (December 2013): 213–27. http://dx.doi.org/10.1142/s1793048013300065.
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Here, we review the properties of a suggested mechanism for a neural ATPase complex based on our recent experimental findings. The mechanism represents a multifunctional ATPase: an enzyme that is a chloride pump and a GABA receptor. This enables new views on the ways Cl - channel transports anions and its regulation by the intra- and extracellular ions and molecules (in particular by glucose, ATP, [Formula: see text]). The hydrolytic activity of this GABA A-coupled ATPase provides the [Formula: see text] transport process the energy and determines a certain direction of ions flux across neuronal membrane. This can help with the research regarding several diseases such as epilepsy. [Formula: see text]Special Issue Comment: This project is about a multifunctional ATPase complex. Experiments involving measuring & solving individual ATPases are related with the Special Issue about FRET experiments,1 about enzymes,2 and about treatments when solving single molecules.3,4 The model suggested here is simply tested with these experimental and mathematical methods.
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Liu, Mengping, Rosalind L. Russell, Leonid Beigelman, Robert E. Handschumacher, and Giuseppe Pizzorno. "β-Alanine and α-fluoro-β-alanine concentrative transport in rat hepatocytes is mediated by GABA transporter GAT-2." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 1 (January 1, 1999): G206—G210. http://dx.doi.org/10.1152/ajpgi.1999.276.1.g206.
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Studies on the compartmentalization of uridine catabolic metabolism in liver have indicated accumulation of β-alanine as well as α-fluoro-β-alanine (FβAL) for 5-fluorouracil in the hepatocytes. Using preparations of rat hepatocytes we were able to identify a Na+-dependent transport with high affinity for β-alanine and GABA with Michaelis constant ( K m) of 35.3 and 22.5 μM, respectively. A second Na+-dependent kinetic component with K m >1 mM was also identified. The sigmoidal profile of β-alanine uptake with respect to Na+ shows the involvement of multiple ions of sodium in the transport process. A Hill coefficient of 2.6 ± 0.4 indicates that at least two sodium ions are cotransported with β-alanine. The flux of β-alanine was also shown to be chlorine dependent. The substitution of this anion with gluconate, even in the presence of Na+, reduced the intracellular concentrative accumulation of β-alanine to passive diffusion level, indicating that both Na+ and Cl− are essential for the activity of this transporter. The transport of β-alanine was inhibited by GABA, hypotaurine, β-aminoisobutyric acid, and FβAL in a competitive manner. However, concentrations up to 1 mM ofl- andd-alanine, taurine, and α-aminoisobutyric acid did not affect β-alanine uptake. Considering the similarities in substrate specificity with the rat GAT-2 transporter, extracts of hepatocytes were probed with the anti-GABA transporter antibody R-22. A 80-kDa band corresponding to GAT-2 was present in the hepatocyte and in the GAT-2 transfected Madin-Darby canine kidney cell extract, confirming the extraneural localization of this transporter. In view of these results, the neurotoxic effects related to the administration of uridine and 5-fluorouracil could be explained with the formation of β-alanine and FβAL and their effect on the cellular reuptake of GABA.
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Hartveit, Espen. "Functional Organization of Cone Bipolar Cells in the Rat Retina." Journal of Neurophysiology 77, no. 4 (April 1, 1997): 1716–30. http://dx.doi.org/10.1152/jn.1997.77.4.1716.
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Hartveit, Espen. Functional organization of cone bipolar cells in the rat retina. J. Neurophysiol. 77: 1716–1730, 1997. The responses of cone bipolar cells in slices of rat retina to ionotropic glutamate receptor agonists were recorded with the whole cell voltage-clamp technique in the presence of 5 mM Co2+ and nominally 0 mM Ca2+ extracellularly. Application of the non- N-methyl-d-aspartate (non-NMDA) receptor agonists kainate and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate had a series of effects on cone bipolar cells (types 1–9), and the different cell types could be classified as on- or off-type cells according to which type(s) of responses they displayed. First, direct responses were observed in cell types 1–4 as short-latency inward currents at −70 mV with reversal potentials ( E revs) close to 0 mV, characteristic of nonselective cation channels. Second, some cells, among types 5–9, did not display short-latency inward currents to kainate at −70 mV. Other type 5–8 cells displayed short-latency kainate responses, but the currents could not be reversed ( E rev of +40 mV or greater). I suggest that these responses are conveyed to the cone bipolar cells through gap junctions, most likely with AII amacrine cells. The lack of reversal is likely due to a substantial voltage drop across the gap junctions resulting in an inadequate voltage control of AII amacrine cells when the recording pipette is on the cone bipolar cell. Kainate responses recorded directly from AII amacrine cells had E rev ∼ 0 mV. Third, long-latency indirect responses selective for chloride ions ( E rev ∼ chloride equilibrium potential) were observed in many cone bipolar cells during longer-lasting application of kainate. The long-latency response component was suppressed by coapplication of the γ-aminobutyric acid-A (GABAA) receptor antagonist picrotoxin and the GABAC receptor antagonist 3-aminopropyl(methyl)phosphinic acid. This long-latency component was absent in axotomized bipolar cells, suggesting that it was due to external Ca2+-independent release of GABA onto the axon terminals of the cone bipolar cells. All kainate-evoked response components were blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Application of NMDA evoked no response in cone bipolar cells. These results suggest that cone bipolar cells types 1–4 are off cone bipolar cells, whereas cone bipolar cells types 5–9 are on cone bipolar cells.
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Houston, C. M., D. P. Bright, L. G. Sivilotti, M. Beato, and T. G. Smart. "Intracellular Chloride Ions Regulate the Time Course of GABA-Mediated Inhibitory Synaptic Transmission." Journal of Neuroscience 29, no. 33 (August 19, 2009): 10416–23. http://dx.doi.org/10.1523/jneurosci.1670-09.2009.
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Cherubini, E., and F. Strata. "GABAC Receptors: A Novel Receptor Family with Unusual Pharmacology." Physiology 12, no. 3 (June 1, 1997): 136–41. http://dx.doi.org/10.1152/physiologyonline.1997.12.3.136.
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GABAC-receptor channels constitute a novel class of structurally defined receptors that are composed by the recently discovered r-subunits. They conduct chloride ions, are insensitive to both bicuculline and baclofen, and are blocked by picrotoxin. They are present in the hippocampus during development and in the retina where they play a crucial role in regulating visual processing.
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Bekar, Lane K., and Wolfgang Walz. "Evidence for Chloride Ions as Intracellular Messenger Substances in Astrocytes." Journal of Neurophysiology 82, no. 1 (July 1, 1999): 248–54. http://dx.doi.org/10.1152/jn.1999.82.1.248.
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Cultured rat hippocampal astrocytes were used to investigate the mechanism underlying the suppression of Ba2+-sensitive K+ currents by GABAAreceptor activation. Muscimol application had two effects on whole cell currents: opening of the well-known Cl− channel of the GABAA receptor and a secondary longer-lasting blockade of outward K+ currents displaying both peak and plateau phases. This blockade was independent of both Na+ (inside and outside) and ATP in the pipette. It also seemed to be independent of muscimol binding to the receptor because picrotoxin application showed no effect on the K+ conductance. The effect is blocked when anion efflux is prevented by replacing Cl−with gluconate (both inside and out) and is enhanced with more permeant anions such as Br− and I−. Moreover, the effect is reproduced in the absence of muscimol by promoting Cl− efflux via lowering of extracellular Cl−levels. These results, along with the requirement for Cl−efflux in muscimol experiments, show a strong dependency of the secondary blockade on Cl− efflux through the Cl− channel of the GABAA receptor. We therefore conclude that changes in the intracellular Cl−concentration alter the outward K+ conductances of astrocytes. Such a Cl−-mediated modulation of an astrocytic K+ conductance will have important consequences for the progression of spreading depression through brain tissue and for astrocytic swelling in pathological situations.
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Huguenard, J. R., and B. E. Alger. "Whole-cell voltage-clamp study of the fading of GABA-activated currents in acutely dissociated hippocampal neurons." Journal of Neurophysiology 56, no. 1 (July 1, 1986): 1–18. http://dx.doi.org/10.1152/jn.1986.56.1.1.
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The lability of the responses of mammalian central neurons to gamma-aminobutyric acid (GABA) was studied using neurons acutely dissociated from the CA1 region of the adult guinea pig hippocampus as a model system. GABA was applied to the neuronal somata by pressure ejection and the resulting current (IGABA) recorded under whole-cell voltage clamp. In initial experiments we examined several basic properties of cells in this preparation. Our data confirm that passive and active membrane properties are similar to those which characterize cells in other preparations. In addition, GABA-dependent conductance (gGABA), reversal potential (EGABA), and the interaction of GABA with pentobarbital and bicuculline all appeared to be normal. Dendritic GABA application could cause depolarizing GABA responses, and somatic GABA application caused hyperpolarizations due to chloride (Cl-) movements. Repetitive brief applications (5-15 ms) of GABA (10(-5) to 10(-3) M) at a frequency of 0.5 Hz led to fading of successive peaks of IGABA until, at a given holding potential, a steady state was reached in which IGABA no longer changed. Imposing voltage steps lasting seconds during a train of steady-state GABA responses led initially to increased IGABA that then diminished with maintenance of the step voltage. The rate of decrease of IGABA at each new holding potential was independent of the polarity of the step in holding potential but was highly dependent on the rate of GABA application. Application rates as low as 0.05 Hz led to fading of IGABA, even with activation of relatively small conductances (5-15 nS). Since IGABA evoked by somatic GABA application in these cells is carried by Cl-, the Cl- equilibrium potential (ECl) is equal to the reversal potential for IGABA, i.e., to EGABA. The fading of IGABA with changes in holding potential can be almost entirely accounted for by a shift in ECl resulting from transmembrane flux of Cl- through the GABA-activated conductance. Maneuvers that prevent changes in the intracellular concentration of Cl-ions, [Cl-]i, including holding the membrane potential at EGABA during repetitive GABA application or buffering [Cl-]i with high pipette [Cl-], prevent changes in EGABA. Desensitization of the GABA response (an actual decrease in gGABA) occurs in these neurons during prolonged application of GABA (greater than 1 s) but with a slower time course than changes in EGABA. Whole-cell voltage-clamp techniques applied to tissue-cultured spinal cord neurons indicated that rapid shifts in EGABA result from repetitive GABA application in these cells as well.(ABSTRACT TRUNCATED AT 250 WORDS)
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Haji, A., J. E. Remmers, C. Connelly, and R. Takeda. "Effects of glycine and GABA on bulbar respiratory neurons of cat." Journal of Neurophysiology 63, no. 5 (May 1, 1990): 955–65. http://dx.doi.org/10.1152/jn.1990.63.5.955.
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1. Bulbar respiratory neurons of unanesthetized, decerebrate cats were impaled with the center pipette of a compound, coaxial microelectrode. This electrode allowed intracellular recording of membrane potential (MP) through the central pipette and extracellular iontophoresis of glycine or gamma-aminobutyric acid (GABA) from micropipettes encircling the center pipette with their tips recessed 20-40 microns from the tip of the center pipette. 2. Seventy-seven studies were carried out on 32 inspiratory and 28 postinspiratory neurons with the use of brief pulses (0.3-0.5 s) or long pulses (3-10 s) spanning one or more respiratory cycles. In both neuronal types, GABA and glycine decreased spike frequency, synaptic "noise," respiratory fluctuations of MP, and "input" resistance in a dose-related fashion. 3. In most cases, the membrane was hyperpolarized by the amino acid. The reverse response (depolarization) was observed when the membrane had been hyperpolarized by current clamp. This reversal from hyperpolarization to depolarization occurred at a MP of -81 +/- 2.3 mV (mean +/- SE, n = 7) for glycine and -81 +/- 1.6 (n = 6) for GABA. 4. After intracellular iontophoresis of chloride ions, application of GABA and glycine depolarized the membrane. 5. During relatively long (3-10 s) periods of iontophoresis of glycine or GABA, the effects on MP and input resistance waned. In some cases (23%), the amino acid depolarized the membrane at the most hyperpolarizated portion of the MP trajectory. This was never observed with brief iontophoretic pulses. Such effects of long duration iontophoresis may reflect changes in membrane properties secondary to the primary action of the amino acid on the membrane of the impaled neuron or indirect synaptic actions via changes in discharge of neighboring neurons. 6. Extracellular iontophoresis of a GABA uptake inhibitor, nipecotic acid, potentiated the effects of GABA. 7. Extracellular application of tetrodotoxin appeared to act pre- and postsynaptically to reduce respiratory fluctuations in membrane potential and to increase input resistance without altering the effects of iontophoresed glycine and GABA, suggesting that the amino acids act on postsynaptic membrane receptors not linked to fast sodium channels.(ABSTRACT TRUNCATED AT 400 WORDS)
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Videv, Pavel, Nikola Mladenov, Tonya Andreeva, Kirilka Mladenova, Veselina Moskova-Doumanova, Georgi Nikolaev, Svetla Petrova, and Jordan Doumanov. "Condensing Effect of Cholesterol on hBest1/POPC and hBest1/SM Langmuir Monolayers." Membranes 11, no. 1 (January 13, 2021): 52. http://dx.doi.org/10.3390/membranes11010052.
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Human bestrophin-1 protein (hBest1) is a transmembrane channel associated with the calcium-dependent transport of chloride ions in the retinal pigment epithelium as well as with the transport of glutamate and GABA in nerve cells. Interactions between hBest1, sphingomyelins, phosphatidylcholines and cholesterol are crucial for hBest1 association with cell membrane domains and its biological functions. As cholesterol plays a key role in the formation of lipid rafts, motional ordering of lipids and modeling/remodeling of the lateral membrane structure, we examined the effect of different cholesterol concentrations on the surface tension of hBest1/POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and hBest1/SM Langmuir monolayers in the presence/absence of Ca2+ ions using surface pressure measurements and Brewster angle microscopy studies. Here, we report that cholesterol: (1) has negligible condensing effect on pure hBest1 monolayers detected mainly in the presence of Ca2+ ions, and; (2) induces a condensing effect on composite hBest1/POPC and hBest1/SM monolayers. These results offer evidence for the significance of intermolecular protein–lipid interactions for the conformational dynamics of hBest1 and its biological functions as multimeric ion channel.
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Maksay, G., and M. K. Ticku. "GABA, depressants and chloride ions affect the rate of dissociation of 35S-t-butylbicyclophosphorothionate binding." Life Sciences 37, no. 23 (December 1985): 2173–80. http://dx.doi.org/10.1016/0024-3205(85)90568-5.
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Vinay, L., J. Y. Barthe, and S. Grillner. "Central modulation of stretch receptor neurons during fictive locomotion in lamprey." Journal of Neurophysiology 76, no. 2 (August 1, 1996): 1224–35. http://dx.doi.org/10.1152/jn.1996.76.2.1224.
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1. In lamprey, stretch receptor neurons (SRNs), also referred to as edge cells, are located along the lateral margin of the spinal cord. They sense the lateral movements occurring in each swim cycle during locomotion. The isolated lamprey spinal cord in vitro was used to investigate the activity of SRNs during fictive locomotion induced by bath-applied N-methyl-D-aspartate (NMDA). Intracellular recordings with potassium acetate filled electrodes showed that 63% of SRNs had a clear locomotor-related modulation of their membrane potential. 2. Of the modulated SRNs, two-thirds had periods of alternating excitation and inhibition occurring during the ipsilateral and the contralateral ventral root bursts, respectively. The phasic hyperpolarization could be reversed into a depolarizing phase after the injection of chloride ions into the cells; this revealed a chloride-dependent synaptic drive. The remaining modulated SRNs were inhibited phasically during ipsilateral motor activity. 3. Experiments with barriers partitioning the recording chamber with the spinal cord into three pools, allowed an inactivation of the locomotor networks within one pool by washing out NMDA from the pool in which the SRN was recorded. This resulted in a marked reduction, but not an abolishment, of the amplitude of the membrane potential oscillations. Both the excitatory and the inhibitory phases were reduced, resulting from removal of input from inhibitory and excitatory interneurons projecting from the adjacent pools. If the glycine receptor antagonist strychnine (1 microM) was applied in one pool, the phasic hyperpolarizing phase disappeared without affecting the excitatory phase. 4. Bath application of the gamma-aminobutyric acid (GABA)A receptor antagonist, bicuculline (50-100 microM) blocked the spontaneous large unitary inhibitory postsynaptic potentials, which occurred without a clear phasic pattern. Bicuculline had no significant effect on the peak to peak amplitude of the locomotor-related membrane potential oscillations. The inhibition in SRNs therefore has a dual origin: glycinergic interneurons provide phasic inhibition, while the GABA system can exert a tonic inhibition via GABAA receptors. 5. These data show that, in addition to the stretch-evoked excitation, which SRNs receive during each locomotor cycle, most of them also receive excitation from the central pattern generator network during the ipsilateral contraction, which may ensure a maintained high level of sensitivity to stretch during the shortening phase of the locomotor cycle. This arrangement is analogous to the efferent control of muscle spindles exerted by gamma-motoneurons in mammals, which as a rule are coactivated with alpha-motoneurons to the same muscle (alpha-gamma linkage).
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Maehara, Taketoshi, Hidenori Suzuki, Koichi Yoshioka, and Masanori Otsuka. "Effect of sodium and chloride ions on substance P-induced release of GABA from the neonatal rat spinal cord." Neuroscience Research Supplements 17 (January 1992): 117. http://dx.doi.org/10.1016/0921-8696(92)90865-x.
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Moroni, M., I. Biro, M. Giugliano, R. Vijayan, P. C. Biggin, M. Beato, and L. G. Sivilotti. "Chloride Ions in the Pore of Glycine and GABA Channels Shape the Time Course and Voltage Dependence of Agonist Currents." Journal of Neuroscience 31, no. 40 (October 5, 2011): 14095–106. http://dx.doi.org/10.1523/jneurosci.1985-11.2011.
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Graf, Werner, Robert Spencer, Harriet Baker, and Robert Baker. "Excitatory and Inhibitory Vestibular Pathways to the Extraocular Motor Nuclei in Goldfish." Journal of Neurophysiology 77, no. 5 (May 1, 1997): 2765–79. http://dx.doi.org/10.1152/jn.1997.77.5.2765.
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Graf, Werner, Robert Spencer, Harriet Baker, and Robert Baker. Excitatory and inhibitory vestibular pathways to the extraocular motor nuclei in goldfish. J. Neurophysiol. 77: 2765–2779, 1997. Electrophysiological, ultrastructural, and immunohistochemical techniques were utilized to describe the excitatory and inhibitory vestibular innervation of extraocular motor nuclei in the goldfish. In antidromically activated oculomotor motoneurons, electrical stimulation of the intact contralateral vestibular nerve produced short-latency, variable amplitude electrotonic excitatory postsynaptic potentials (EPSPs) at 0.5–0.7 ms followed by chemical EPSPs at 1.0–1.3 ms. Stimulation of the ipsilateral vestibular nerve produced small amplitude membrane hyperpolarizations at a latency of 1.3–1.7 ms in which equilibrium potentials were slightly more negative than resting potentials. The inhibitory postsynaptic potentials (IPSPs) reversed with large amplitudes after the injection of chloride ions suggesting a proximal soma-dendritic location of terminals exhibiting high efficacy inhibitory synaptic conductances. In antidromically identified abducens motoneurons and putative internuclear neurons, electrical stimulation of the contralateral vestibular nerve produced large-amplitude, short-latency electrotonic EPSPs at 0.5 ms followed by chemical depolarizations at 1.2–1.3 ms. Stimulation of the ipsilateral vestibular nerve evoked IPSPs at 1.4 ms that were reversed after injection of current and/or chloride ions. γ-Aminobutyric acid (GABA) antibodies labeled inhibitory neurons in vestibular subdivisions with axons projecting into the ipsilateral medial longitudinal fasciculus (MLF). Putative GABAergic terminals surrounded oculomotor, but not abducens, motoneurons retrogradely labeled with horseradish peroxidase. Hence the spatial distribution of GABAergic neurons and terminals appears highly similar in the vestibuloocular system of goldfish and mammals. Electron microscopy of motoneurons in the oculomotor and abducens nucleus showed axosomatic and axodendritic synaptic endings containing spheroidal synaptic vesicles establishing chemical, presumed excitatory, synaptic contacts with asymmetric pre- and/or postsynaptic membrane specializations. The majority of contacts with spheroidal vesicles displayed gap junctions in which the chemical and electrotonic synapses were either en face to dissimilar or adjacent to one another on the same soma/dendritic profiles. Another separate set of axosomatic synaptic endings, presumed to be inhibitory, contained pleiomorphic synaptic vesicles with symmetric pre- and/or postsynaptic membrane specializations that never included gap junctions. Excitatory and inhibitory synaptic contacts appeared equal in number but were more sparsely distributed along the soma-dendritic profiles of oculomotor as compared with abducens motoneurons. Collectively these data provide evidence for both disynaptic vestibular inhibition and excitation in all subdivisions of the extraocular motor nuclei suggesting the basic vestibulooculomotor blueprint to be conserved among vertebrates. We propose that unique vestibular neurons, transmitters, pathways, and synaptic arborizations are homologous structural traits that have been essentially preserved throughout vertebrate phylogeny by a shared developmental plan.
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Borst, J. G., J. C. Lodder, and K. S. Kits. "Large amplitude variability of GABAergic IPSCs in melanotropes from Xenopus laevis: evidence that quantal size differs between synapses." Journal of Neurophysiology 71, no. 2 (February 1, 1994): 639–55. http://dx.doi.org/10.1152/jn.1994.71.2.639.
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1. We made in situ whole-cell recordings from melanotropes in the intermediate lobe of the pituitary gland of Xenopus laevis. Melanotropes received spontaneous synaptic inputs that had a fast rise time and a much slower decay. These inputs were GABAergic inhibitory postsynaptic currents (IPSCs): they followed the reversal potential for chloride ions and they were blocked by the gamma-aminobutyric acid-A (GABAA) receptor antagonist bicuculline. 2. Because of the very low baseline noise it was possible to see discrete levels in the tails of IPSCs that corresponded to the opening of one or more synaptic GABAA receptor channels. "All-points" histograms of the IPSCs showed that the chord conductance of the channels in the tails of the IPSCs was 21.6 +/- 0.6 pS (mean +/- SE, n = 6). 3. The amplitudes of the spontaneous IPSCs were very variable, ranging from 3 to 390 pA at a holding potential of -80 mV. The average of the median amplitudes was -67.5 +/- 5.9 pA (n = 28). The amplitude distributions of the IPSCs were well described by the sum of two lognormal distributions with large SDs. The average of the means of the first lognormal distribution was 27.8 +/- 5.3 pA (n = 10); the average of the SDs was 24.7 +/- 8.1 pA. For the second lognormal distribution these values were 87.0 +/- 13.4 and 33.7 +/- 7.4 pA. An average of 41.8 +/- 6.9% of the IPSCs originated from the first lognormal distribution. 4. The large variability in the amplitudes of spontaneous IPSCs was not the result of presynaptic action potentials because it was not reduced by tetrodotoxin (TTX), Ca(2+)-free extracellular solution, or the combined application of TTX and Mn2+. 5. The time course of the IPSCs from the first and the second lognormal distributions were very similar: averages of the median 20- to 80% rise times were 585 +/- 64 and 488 +/- 28 microseconds, respectively (n = 8), whereas the decays were well described by the sum of two exponential functions, with fast time constants of 8.9 +/- 1.1 (n = 7) and 9.3 +/- 3.3 ms and slow time constants of 29.5 +/- 3.3 and 31.7 +/- 2.6 ms, respectively. 6. The decay of the IPSCs was voltage dependent; it was approximately 3 times slower at a holding potential of +40 mV than at -80 mV (n = 5).(ABSTRACT TRUNCATED AT 400 WORDS)
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Graf, Werner, Robert Spencer, Harriet Baker, and Robert Baker. "Vestibuloocular Reflex of the Adult Flatfish. III. A Species-Specific Reciprocal Pattern of Excitation and Inhibition." Journal of Neurophysiology 86, no. 3 (September 1, 2001): 1376–88. http://dx.doi.org/10.1152/jn.2001.86.3.1376.
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In juvenile flatfish the vestibuloocular reflex (VOR) circuitry that underlies compensatory eye movements adapts to a 90° relative displacement of vestibular and oculomotor reference frames during metamorphosis. VOR pathways are rearranged to allow horizontal canal-activated second-order vestibular neurons in adult flatfish to control extraocular motoneurons innervating vertical eye muscles. This study describes the anatomy and physiology of identified flatfish-specific excitatory and inhibitory vestibular pathways. In antidromically identified oculomotor and trochlear motoneurons, excitatory postsynaptic potentials (EPSPs) were elicited after electrical stimulation of the horizontal canal nerve expected to provide excitatory input. Electrotonic depolarizations (0.8–0.9 ms) preceded small amplitude (<0.5 mV) chemical EPSPs at 1.2–1.6 ms with much larger EPSPs (>1 mV) recorded around 2.5 ms. Stimulation of the opposite horizontal canal nerve produced inhibitory postsynaptic potentials (IPSPs) at a disynaptic latency of 1.6–1.8 ms that were depolarizing at membrane resting potentials around −60 mV. Injection of chloride ions increased IPSP amplitude, and current-clamp analysis showed the IPSP equilibrium potential to be near the membrane resting potential. Repeated electrical stimulation of either the excitatory or inhibitory horizontal canal vestibular nerve greatly increased the amplitude of the respective synaptic responses. These observations suggest that the large terminal arborizations of each VOR neuron imposes an electrotonic load requiring multiple action potentials to maximize synaptic efficacy. GABA antibodies labeled axons in the medial longitudinal fasciculus (MLF) some of which were hypothesized to originate from horizontal canal-activated inhibitory vestibular neurons. GABAergic terminal arborizations were distributed largely on the somata and proximal dendrites of oculomotor and trochlear motoneurons. These findings suggest that the species-specific horizontal canal inhibitory pathway exhibits similar electrophysiological and synaptic transmitter profiles as the anterior and posterior canal inhibitory projections to oculomotor and trochlear motoneurons. Electron microscopy showed axosomatic and axodendritic synaptic endings containing spheroidal synaptic vesicles to establish chemical excitatory synaptic contacts characterized by asymmetrical pre/postsynaptic membrane specializations as well as gap junctional contacts consistent with electrotonic coupling. Another type of axosomatic synaptic ending contained pleiomorphic synaptic vesicles forming chemical, presumed inhibitory, synaptic contacts on motoneurons that never included gap junctions. Altogether these data provide electrophysiological, immunohistochemical, and ultrastructural evidence for reciprocal excitatory/inhibitory organization of the novel vestibulooculomotor projections in adult flatfish. The appearance of unique second-order vestibular neurons linking the horizontal canal to vertical oculomotor neurons suggests that reciprocal excitation and inhibition are a fundamental, developmentally linked trait of compensatory eye movement circuits in vertebrates.
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Deuchars, Susan A., K. Michael Spyer, and Michael P. Gilbey. "Stimulation Within the Rostral Ventrolateral Medulla Can Evoke Monosynaptic GABAergic IPSPs in Sympathetic Preganglionic Neurons In Vitro." Journal of Neurophysiology 77, no. 1 (January 1, 1997): 229–35. http://dx.doi.org/10.1152/jn.1997.77.1.229.
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Deuchars, Susan A., K. Michael Spyer, and Michael P. Gilbey. Stimulation within the rostral ventrolateral medulla can evoke monosynaptic GABAergic IPSPs in sympathetic preganglionic neurons in vitro. J. Neurophysiol. 77: 229–235, 1997. The inhibitory responses of identified sympathetic preganglionic neurons (SPNs) to stimulation within the rostral ventrolateral medulla (RVLM) were studied to determine their nature and pharmacology. Whole cell patch-clamp recordings were made from 36 SPNs in the upper thoracic segments of the spinal cord in a neonatal rat brain stem-spinal cord preparation. Neurons were identified as SPNs on the basis of their antidromic activation after stimulation of the ipsilateral segmental ventral root and their morphology and location in the intermediolateral cell column and intercalated nucleus. In all SPNs, electrical stimulation of the RVLM evoked fast excitatory postsynaptic potentials (EPSPs) that were mediated by non- N-methyl-d-aspartate (NMDA) and NMDA receptors. These excitatory responses were the most prominent response in control artificial cerebrospinal fluid and have been studied previously. In 22 of the SPNs, RVLM stimulation also elicited fast inhibitory postsynaptic potentials (IPSPs), which increased in amplitude as the membrane was depolarized. Five of these neurons were not studied further as they responded occasionally with IPSPs that had highly variable onset latencies indicating the involvement of a polysynaptic pathway. In the remaining SPNs ( n = 17), the evoked IPSPs persisted in the presence of the excitatory amino acid antagonists 6-cyano-7-nitroquinoxaline-2,3,-dione and d,l-2-amino-5-phosphonopentanoic acid. In eight of these SPNs, it was necessary to block the EPSPs to reveal the IPSPs. In the 7 SPNs tested, the onset latencies of the IPSPs were not significantly different from the onset latencies of the fast EPSPs. The low sweep-to-sweep fluctuations in onset latency of individual IPSPs (absolute average deviation: 0.4 ms) indicated that the IPSPs were elicited by activation of a monosynaptic pathway. The amplitudes of the IPSPs decreased in amplitude as the membrane was hyperpolarized and reversed in polarity at −70.3 ± 1.7 mV (mean ± SD), which was close to the equilibrium potential for chloride ions. In addition, in seven SPNs, bath applications of 5 μM bicuculline, a γ-aminobuturic acid-A (GABAA) antagonist, abolished or reduced the evoked IPSPs. Five SPNs also were studied that displayed ongoing IPSPs. The amplitudes of these IPSPs increased with membrane depolarization and were blocked by bath applications of 5 μM bicuculline, suggesting that they also were mediated by activation of GABAA receptors. These results demonstrate the existence of a bulbospinal GABAergic pathway impinging directly onto SPNs. This pathway may be tonically active in the neonatal rat brain stem-spinal cord preparation.
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"Ionic events following GABA receptor activation in an identified insect motor neuron." Proceedings of the Royal Society of London. Series B. Biological Sciences 232, no. 1269 (January 22, 1988): 457–70. http://dx.doi.org/10.1098/rspb.1988.0007.
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The ionic events underlying γ-aminobutyric acid (GABA) receptor activation on the cell body of a cockroach identified motor neuron were investigated by using current-clamp and voltage-clamp techniques. The reversal potential for GABA-induced hyperpolarization was –77.0 ± 2.4 mV (mean ± s. e. m.; n = 22). The reversal potential for GABA was highly sensitive to changes in external chloride, only weakly affected by changes in external potassium, and independent of changes in either sodium or calcium ion concentration. Intracellular ion-sensitive microelectrodes confirmed that an influx of chloride ions mediated the GABA response. Intracellular injection of acetate, citrate, sulphate, fluoride or ammonium caused no change in the reversal potential for GABA. Intracellular injection of chloride, bromide, chlorate, bromate, or methyl sulphate shifted the reversal potential for GABA to values more positive than resting membrane potential. Evidence for chloride accumulating and for extrusion mechanisms was examined by using putative inhibitors. However, internal application of ammonium ions, and external application of 4-acetamido-4'-isothiocyanatostilbene-2, 2'-disulphonic acid (SITS), 4, 4'-diisothiocyanatostilbene-2, 2'-disulphonic acid (DIDS), acetazolamide, furosemide, ammonium, zinc and copper ions, were all without effect on the reversal potential for GABA.
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"GABA receptors on the cell-body membrane of an identified insect motor neuron." Proceedings of the Royal Society of London. Series B. Biological Sciences 232, no. 1269 (January 22, 1988): 443–56. http://dx.doi.org/10.1098/rspb.1988.0006.
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The pharmacology of a γ-aminobutyric acid (GABA) receptor on the cell body of an identified motor neuron of the cockroach ( Periplaneta americana ) was investigated by current-clamp and voltage-clamp methods. Iontophoretic application of GABA increased membrane conductance to chloride ions, and prolonged application resulted in desensitization. Hill coefficients, determined from dose–response data, indicated that binding of at least two GABA molecules was required to activate the chloride channel. Differences between vertebrate GABA A receptors and insect neuronal GABA receptors were detected. For the GABA receptor of motor neuron D f , the following rank order of potency was observed: isoguvacine > muscimol ≽ GABA > 3-aminopropanesulphonic acid. The GABA B receptor agonist baclofen was inactive. Of the potent vertebrate GABA receptor antagonists (bicuculline, pitrazepin, RU5135 and picrotoxin), only picrotoxin (10 –7 M) produced a potent, reversible block of the response to GABA of motor neuron D f . Both picrotoxinin and picrotin also blocked GABA-induced currents. Bicuculline hydrochloride (10 –4 M) and bicuculline methiodide (10 –4 M) were both ineffective when applied at resting membrane potential (–65 mV), although at hyper-polarized levels partial block of GABA-induced current was sometimes observed. Pitrazepin (10 –4 M) caused a partial, voltage-independent block of GABA-induced current. The steroid derivative RU5135 was inactive at 10 –5 M. In contrast to the potent competitive blockade of vertebrate GABA A receptors by bicuculline, pitrazepin and RU5135, none of the weak antagonism caused by these drugs on the insect GABA receptor was competitive. Flunitrazepam (10 –6 M) potentiated GABA responses, providing evidence for a benzodiazepine site on an insect GABA-receptor–chloride-channel complex.
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Alqarawi, Abdulaziz Abdullah, Abeer Hashem, Elsayed Fathi Abd_Allah, Asma A. Al-Huqail, Thobayet Safr Alshahrani, Sa'ad Rukban Alshalawi, and Dilfuza Egamberdieva. "Protective role of gamma amminobutyric acid on Cassia italica Mill under salt stress." Legume Research - An International Journal, OF (April 9, 2016). http://dx.doi.org/10.18805/lr.v0iof.9561.
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The present study was conducted to evaluate the effect of salinity stress on growth of Cassia italica and role of gamma amminobutyric acid (GABA) in mitigating the salt stress induced damaging effects. Antioxidant activity, level of endogenous growth hormones and other biochemical parameters were evaluated. Salt stress enhanced the production of reactive oxygen species (ROS) resulting in the enhanced lipid peroxidation which was however reduced by application of GABA. Increased lipid peroxidation in salt stressed plants caused an obvious reduction in the total lipid content as compared to GABA treated plants. The antioxidant enzymes were higher in GABA treated plants which indicated a reduction of oxidative damage. The concentrations of growth hormones like indole acetic acid (IAA), indole butyric acid (IBA), gibberellic acid-1 (GA1), and gibberellic acid-4 (GA4) were reduced by salt stress, while enhanced by GABA treatment. In addition GABA treated plants maintained lower levels of sodium and chloride ions as compared to salt stressed plants. It could be concluded that toxic effects of salt stress on growth, antioxidant system, hormones and mineral nutrients in Cassia italica could be alleviated by exogenous application of GABA.
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Mareš, P. "Age- and dose-specific anticonvulsant action of bumetanide in immature rats." Physiological Research, 2009, 927–30. http://dx.doi.org/10.33549/physiolres.931897.
Full textAbstract:
GABA exhibits depolarizing action in the immature neurons due to high intracellular activity of chloride ions. It is maintained by cation-chloride cotransporter NKCC1 which is present in immature brain. Bumetanide is a specific inhibitor of this cotransporter. We studied possible anticonvulsant activity of bumetanide in pentylenetetrazol-induced seizures in three age groups of rat pups (7, 12, and 18 days old). Pretreatment with bumetanide (0.2-1 mg/kg i.p.) resulted in dose-dependent decrease of incidence of the tonic phase of generalized tonicclonic seizures in 12-day-old rats only. No effect was observed in younger and older animals. Higher dose of bumetanide (2.5 mg/kg) did not affect tonic convulsions but, on the contrary, decreased latencies of generalized seizures in 12-day-old animals. Lack of marked anticonvulsant effect is probably due to relative maturity of neurons in the brainstem where the generator of generalized seizures is localized. Age- and dosespecific suppression of the tonic phase needs further analysis.