Journal articles on the topic 'GABA'
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1
Akasu, Takashi, Yoshikazu Munakata, Masashi Tsurusaki, and Hiroshi Hasuo. "Role of GABAA and GABAC Receptors in the Biphasic GABA Responses in Neurons of the Rat Major Pelvic Ganglia." Journal of Neurophysiology 82, no. 3 (September 1, 1999): 1489–96. http://dx.doi.org/10.1152/jn.1999.82.3.1489.
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The role of γ-aminobutyric acid-A (GABAA) and GABAC receptors in the GABA-induced biphasic response in neurons of the rat major pelvic ganglia (MPG) were examined in vitro. Application of GABA (100 μM) to MPG neurons produced a biphasic response, an initial depolarization (GABAd) followed by a hyperpolarization (GABAh). The input resistance of the MPG neurons was decreased during the GABAd, whereas it was increased during the GABAh. The GABAd could be further separated into the early component (early GABAd) with a duration of 27 ± 5 s (mean ± SE; n = 11) and the late component (late GABAd) with a duration of 109 ± 11 s ( n = 11). The duration of the GABAh was 516 ± 64 s ( n = 11). The effects of GABA (5–500 μM) in producing the depolarization and the hyperpolarization were concentration-dependent. GABA (5–30 μM) induced only late depolarizations. The early component of the depolarization appeared when the concentration of GABA was >50 μM. Muscimol produced only early depolarizing responses. Baclofen (100 μM) had no effect on the membrane potential and input resistance of MPG neurons. Bicuculline (60 μM) blocked the early GABAdbut not the late GABAd and the GABAh. Application of picrotoxin (100 μM) with bicuculline (60 μM) blocked both the late GABAd and the GABAh. CGP55845A (3 μM), a selective GABAB receptor antagonist, did not affect the GABA-induced responses. cis-4-Aminocrotonic acid (CACA, 1 mM) and trans-4-aminocrotonic acid (TACA, 1 mM), selective GABAC receptor agonists, produced late biphasic responses in the MPG neurons. The duration of the CACA responses was almost the same as those of the late GABAdand GABAh obtained in the presence of bicuculline. Imidazole-4-acetic acid (I4AA, 100 μM), a GABAC receptor antagonist, depressed the late GABAd and the GABAh but not the early GABAd. I4AA (100 μM) and picrotoxin (100 μM) also suppressed the biphasic response to CACA. The early GABAd and the late GABAd were reversed in polarity at −32 ± 3 mV ( n = 7) and −38 ± 2 mV ( n = 4), respectively, in the Krebs solution. The reversal potential of the GABAh was −34 ± 2 mV ( n = 4) in the Krebs solution. The reversal potentials of the late GABAd and the GABAh shifted to −20 ± 3 mV ( n = 5) and −22 ± 3 mV ( n = 5), respectively, in 85 mM Cl− solution. These results indicate that the late GABAd and the GABAh are mediated predominantly by bicuculline-insensitive, picrotoxin-sensitive GABA receptors, GABAC (or GABAAOr) receptors, in neurons of the rat MPG.
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Qian, H., and J. E. Dowling. "GABAA and GABAC receptors on hybrid bass retinal bipolar cells." Journal of Neurophysiology 74, no. 5 (November 1, 1995): 1920–28. http://dx.doi.org/10.1152/jn.1995.74.5.1920.
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1. gamma-Aminobutyric acid (GABA) responses from solitory hybrid bass retinal bipolar cells were studied with the use of conventional and perforated whole cell patch-clamp recording. 2. GABA elicited a chloride current in bipolar cells that had both transient and sustained components. The transient component was sensitive to bicuculline and resembled GABAA-mediated currents, whereas the more sustained component was resistant to bicuculline and resembled the responses mediated by GABAC receptors. 3. The bicuculline-resistant GABA responses recorded from the bipolar cells could not be modulated by either diazepam or pentobarbital sodium, and they were unaffected by phaclofen and 2-hydroxysaclofen, GABAB receptor antagonists. On the other hand, the bicuculline-resistant GABA responses could be blocked substantially by imidazole-4-acetic acid (I4AA), a competitive antagonist of GABAC receptors. 4. Noise analysis of the GABA-elicited currents suggested a different single channel conductance for GABAA (10.1 pS) and GABAC receptors (3.6 pS). 5. Zinc, a putative modulator of synaptic transmission, strongly inhibited the GABAC responses on bipolar cells, whereas the GABAA responses were not significantly affected by zinc. 6. The proportion of the GABAC to GABAA responses varied widely between bipolar cells. Local application of GABA onto dendrites or axon terminals showed that both types of GABA receptors are present on both regions of the cell. 7. The distinct properties of these two GABA receptor types suggest that they play different roles in retinal function.
3
Jackel, C., W. Krenz, and F. Nagy. "BICUCULLINE/BACLOFEN-INSENSITIVE GABA RESPONSE IN CRUSTACEAN NEURONES IN CULTURE." Journal of Experimental Biology 191, no. 1 (June 1, 1994): 167–93. http://dx.doi.org/10.1242/jeb.191.1.167.
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Neurones were dissociated from thoracic ganglia of embryonic and adult lobsters and kept in primary culture. When gamma-aminobutyric acid (GABA) was applied by pressure ejection, depolarizing or hyperpolarizing responses were produced, depending on the membrane potential. They were accompanied by an increase in membrane conductance. When they were present, action potential firing was inhibited. The pharmacological profile and ionic mechanism of GABA-evoked current were investigated under voltage-clamp with the whole-cell patch-clamp technique. The reversal potential of GABA-evoked current depended on the intracellular and extracellular Cl- concentration but not on extracellular Na+ and K+. Blockade of Ca2+ channels by Mn2+ was also without effect. The GABA-evoked current was mimicked by application of the GABAA agonists muscimol and isoguvacine with an order of potency muscimol>GABA>isoguvacine. cis-4-aminocrotonic acid (CACA), a folded and conformationally restricted GABA analogue, supposed to be diagnostic for the vertebrate GABAC receptor, also induced a bicuculline-resistant chloride current, although with a potency about 10 times lower than that of GABA. The GABA-evoked current was largely blocked by picrotoxin, but was insensitive to the GABAA antagonists bicuculline, bicuculline methiodide and SR 95531 at concentrations of up to 100 µmol l-1. Diazepam and phenobarbital did not exert modulatory effects. The GABAB antagonist phaclophen did not affect the GABA-induced current, while the GABAB agonists baclophen and 3-aminopropylphosphonic acid (3-APA) never evoked any response. Our results suggest that lobster thoracic neurones in culture express a chloride-conducting GABA-receptor channel which conforms to neither the GABAA nor the GABAB types of vertebrates but shows a pharmacology close to that of the novel GABAC receptor described in the vertebrate retina.
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Zhang, J., and M. M. Slaughter. "Preferential suppression of the ON pathway by GABAC receptors in the amphibian retina." Journal of Neurophysiology 74, no. 4 (October 1, 1995): 1583–92. http://dx.doi.org/10.1152/jn.1995.74.4.1583.
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1. Electrophysiological recordings were obtained from neurons in the amphibian intact retina and retinal slice preparations. The effects of gamma-aminobutyric acid (GABA) were evaluated in the presence of bicuculline or SR95531, which block the GABAA receptor, and baclofen, which saturates the GABAB receptor. 2. Under these conditions, GABA preferentially reduced ON light responses in amacrine and ganglion cells, apparently through a presynaptic mechanism that reduced bipolar cell input. GABA also produced a small hyperpolarization in the resting membrane potential of ganglion cells. 3. Picrotoxin blocked these effects of GABA. The action of GABA was duplicated by muscimol and by trans-aminocrotonic acid. Cis-aminocrotonic acid was neither a potent nor selective agonist. This pharmacology is indicative of the GABAC receptor. 4. In voltage-clamp recordings of ganglion cells in the slice preparation, GABA produced a large chloride conductance that was blocked by bicuculline or SR95531, and a smaller chloride conductance that was not blocked by these GABAA receptor antagonists, but was blocked by picrotoxin. This indicates that ganglion cells possess both GABAA and GABAC receptors. 5. The GABAC receptor current was relatively nondesensitized. Consequently, whereas the peak GABAA receptor current was more than fivefold larger than the GABAC receptor current, after desensitization the latter current was larger. Both currents reversed near the chloride equilibrium potential.
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Naffaa, Moawiah M., David E. Hibbs, Mary Chebib, and Jane R. Hanrahan. "Pharmacological Effect of GABA Analogues on GABA-ϱ2 Receptors and Their Subtype Selectivity." Life 12, no. 1 (January 17, 2022): 127. http://dx.doi.org/10.3390/life12010127.
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GABAϱ receptors are distinctive GABAergic receptors from other ionotropic GABAA and metabotropic GABAB receptors in their pharmacological, biochemical, and electrophysiological properties. Although GABA-ϱ1 receptors are the most studied in this subfamily, GABA-ϱ2 receptors are widely distributed in the brain and are considered a potential target for treating neurological disorders such as stroke. The structure of GABA-ϱ2 receptors and their pharmacological features are poorly studied. We generated the first homology model of GABA-ϱ2 channel, which predicts similar major interactions of GABA with the binding-site residues in GABA-ϱ1 and GABA-ϱ2 channels. We also investigated the pharmacological properties of several GABA analogues on the activity of GABA-ϱ2 receptors. In comparison to their pharmacological effect on GABA-ϱ1 receptors, the activation effect of these ligands and their potentiation/inhibition impact on GABA response have interestingly shown inter-selectivity between the two GABA-ϱ receptors. Our results suggest that several GABA analogues can be used as research tools to study the distinctive physiology of GABA-ϱ1 and GABA-ϱ2 receptors. Furthermore, their partial agonist effect may hold promise for the future discovery of selective modulatory agents on GABAA receptors.
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ROTOLO, THOMAS C., and RAMON F. DACHEUX. "Two neuropharmacological types of rabbit ON-alpha ganglion cells express GABAC receptors." Visual Neuroscience 20, no. 4 (July 2003): 373–84. http://dx.doi.org/10.1017/s095252380320403x.
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The major inhibitory neurotransmitters GABA and glycine provide the bulk of input to large-field ganglion cells in the retina. Whole-cell patch-clamp recordings were used to characterize the glycine- and GABA-activated currents for morphologically identified ON-α ganglion cells in the rabbit retina. Cells identified as ON-α cells by light evoked currents were intracellularly stained and examined by light microscopy which revealed dendritic stratification in the vitreal half of the inner plexiform layer and confirmed their physiological identity. All Ca2+-mediated synaptic influences were abolished with Co2+, revealing two types of ON-α cell characterized by their different inhibitory current profiles. One group exhibited larger glycine- than GABA-activated currents, while the other group had larger GABA- than glycine-activated currents. Both cell types demonstrated strychnine-sensitive glycine-activated currents and bicuculline-sensitive GABAA-activated currents. Surprisingly, both cell types expressed functional GABAC receptors demonstrated by their sensitivity to TPMPA. In addition, the cells with larger glycine-activated currents also possessed GABAB receptors, whereas those with larger GABA-activated currents did not. Immunocytochemical experiments confirmed the presence of glycine, GABAA, and GABAC receptor subunits on all physiologically identified ON-α ganglion cells in this study. In addition, the GABAB receptor immunolabeled puncta were present on the cells with larger glycine-activated currents, but not on the cells with the larger GABA-activated currents. In conclusion, the presence of different functional GABA and glycine receptors determined physiologically correlated well with the specific GABA and glycine receptor immunolabeling for two neuropharmacological types of rabbit ON-α ganglion cells.
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Absalom, Nathan, Izumi Yamamoto, David O'Hagan, Luke Hunter, and Mary Chebib. "Probing the Mode of Neurotransmitter Binding to GABA Receptors Using Selectively Fluorinated GABA Analogues." Australian Journal of Chemistry 68, no. 1 (2015): 23. http://dx.doi.org/10.1071/ch14456.
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Stereoselective fluorination is a useful technique for controlling the conformations of organic molecules. This concept has been exploited to create conformationally biased analogues of the neurotransmitter gamma-aminobutyric acid (GABA). Mono- and di-fluorinated GABA analogues are found to adopt different conformations, due to subtle stereoelectronic effects associated with the C–F bond. These conformationally biased GABA analogues exhibit different shape-dependent selectivity patterns towards GABAA, GABAB, and GABAC receptors, providing valuable information on the binding modes of the natural ligand at these medicinally important targets.
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Han, Y., D. Cao, X. Li, R. Zhang, F. Yu, Y. Ren, and L. An. "Attenuation of γ-aminobutyric acid (GABA) transaminase activity contributes to GABA increase in the cerebral cortex of mice exposed to β-cypermethrin." Human & Experimental Toxicology 33, no. 3 (November 12, 2013): 317–24. http://dx.doi.org/10.1177/0960327113497770.
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The current study investigated the γ-aminobutyric acid (GABA) levels and GABA metabolic enzymes (GABA transaminase (GABAT) and glutamate decarboxylase (GAD)) activities at 2 and 4 h after treatment, using a high-performance liquid chromatography with ultraviolet detectors and colorimetric assay, in the cerebral cortex of mice treated with 20, 40 or 80 mg/kg β-cypermethrin by a single oral gavage, with corn oil as vehicle control. In addition, GABA protein (4 h after treatment), GABAT protein (2 h after treatment) and GABA receptors messenger RNA (mRNA) expression were detected by immunohistochemistry, Western blot and real-time quantitative reverse transcriptase polymerase chain reaction, respectively. β-Cypermethrin (80 mg/kg) significantly increased GABA levels in the cerebral cortex of mice, at both 2 and 4 h after treatment, compared with the control. Also, GABA immunohistochemistry results suggested that the number of positive granules was increased in the cerebral cortex of mice 4 h after exposure to 80 mg/kg β-cypermethrin when compared with the control. Furthermore, the results also showed that GABAT activity detected was significantly decreased in the cerebral cortex of mice 2 h after β-cypermethrin administration (40 or 80 mg/kg). No significant changes were found in GAD activity, or the expression of GABAT protein and GABAB receptors mRNA, in the cerebral cortex of mice, except that 80 mg/kg β-cypermethrin caused a significant decrease, compared with the vehicle control, in GABAA receptors mRNA expression 4 h after administration. These results suggested that attenuated GABAT activity induced by β-cypermethrin contributed to increased GABA levels in the mouse brain. The downregulated GABAA receptors mRNA expression is most likely a downstream event.
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Liske, S., and M. E. Morris. "Extrasynaptic effects of GABA (γ-aminobutyric acid) agonists on myelinated axons of peripheral nerve." Canadian Journal of Physiology and Pharmacology 72, no. 4 (April 1, 1994): 368–74. http://dx.doi.org/10.1139/y94-054.
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Effects of the inhibitory neurotransmitter, GABA (γ-aminobutyric acid) on the excitability of myelinated fibers of isolated amphibian sciatic nerves and their dorsal and ventral spinal roots have been compared with those of a GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), and the GABAB agonist baclofen. Graded, prolonged increases in the amplitude of A-fiber half-maximal compound action potentials of Rana ballenderi sciatic nerves were evoked by GABA (Rmax = 49%, EC50 = 0.1 mM); responses to THIP were smaller (Rmax = 34%, EC50 = 1.1 mM) and with a different, distinctly biphasic recovery phase. In studies of Rana catesbeiana nerves and their attached spinal roots, excitability increases produced in fibers of the ventral roots by GABA were smaller than those of the dorsal roots. Peak changes evoked by THIP in both roots were similar to the effects of GABA on the ventral root; however, THIP's ventral root response showed much less sensitivity and was followed by a rapid recovery phase, undershoot, and secondary, prolonged enhancement. Bicuculline methiodide antagonized agonist-induced increases, and revealed the presence of significant decreases in excitability of the ventral root fibers at concentrations of GABA or THIP < 3 mM. Baclofen evoked inconsistent changes in the excitability of whole nerve and root fibers; small increases occurred with lower doses and secondary, delayed decreases with higher doses. The high concentration (≥ 0.1 mM) of the active isomer needed to cause a small response suggests a limited contribution and (or) presence of GABAB receptors. GABA and its agonists evoke complex, multiphasic excitability changes in the myelinated axons of the spinal roots and peripheral nerve. Contributions of different phases of increase and directions of change signify the participation of multiple receptors and (or) mechanisms. Responses of the dorsal root appear to reflect mainly GABAA-mediated increases in excitability; those of the ventral root include an additional or greater decrease, which may reflect a hyperpolarizing component mediated by a GABAC-like or bicuculline methiodide insensitive GABAA receptor. The large, prolonged responses of the sensory axons to GABA may be linked to their greater K+ channel conductance and related to the inhibitory transmitter's depolarizing action at the more proximal site of their central presynaptic terminals.Key words: dorsal and ventral roots, amphibian, excitability, GABAA, GABAB, GABAC.
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Fischer, Y., and I. Parnas. "Activation of GABAB receptors at individual release boutons of the crayfish opener neuromuscular junction produces presynaptic inhibition." Journal of Neurophysiology 75, no. 4 (April 1, 1996): 1377–85. http://dx.doi.org/10.1152/jn.1996.75.4.1377.
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1. Presynaptic inhibition in crustaceans involves the activation of gamma-aminobutyric acid-A (GABAA) receptors that produce an increase in chloride conductance at excitatory axon terminals. Such inhibition produced by single inhibitory pulses is blocked by picrotoxin, a GABAA antagonist. 2. Presynaptic inhibition produced by bath application of GABA was not blocked by picrotoxin. Measurements of the membrane resistance of the excitatory axon terminals revealed that substantial presynaptic inhibition still persisted after 50 microM picrotoxin had completely blocked the increase in conductance produced by 10 microM GABA. 3. Baclofen, a GABAB agonist, reduced release from the excitatory nerve terminals, and 20H-Saclofen, a GABAB antagonist, blocked the effect of baclofen and the presynaptic inhibition produced by 10 microM GABA. 4. 20H-Saclofen alone did not block presynaptic inhibition produced by 100 microM GABA, and the combined action of both 20H-Saclofen and picrotoxin was required to block such effects. 5. The excitatory nerve terminals seem to contain GABAA and GABAB receptors. The GABAB receptors are preferentially activated at lower GABA concentrations (in the microM range), whereas both the GABAA and GABAB receptors are activated at high GABA concentrations.
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McGILLEM, GREGORY S., THOMAS C. ROTOLO, and RAMON F. DACHEUX. "GABA responses of rod bipolar cells in rabbit retinal slices." Visual Neuroscience 17, no. 3 (May 2000): 381–89. http://dx.doi.org/10.1017/s0952523800173067.
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GABAergic responses of rabbit rod bipolar cells were reexamined by using whole-cell recordings in the superfused slice preparation to determine if there is GABAC receptor input to their axon terminal and to characterize the contribution that GABAA and GABAC receptors make to the total GABA current on the axon terminals of these cells. Pharmacological agents specifically blocking GABAA and GABAC receptor currents demonstrated that 37% of the GABA-activated current was blocked by either the GABAA antagonists bicuculline or SR-95531, whereas the remaining 63% of the GABA current was blocked by a mixture of bicuculline and the GABAC antagonist TPMPA. This indicated that GABAC receptors were present on the axon terminal of the rabbit rod bipolar cell and that they were responsible for mediating the bicuculline insensitive GABA current.
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Hare, W. A., and W. G. Owen. "Receptive field of the retinal bipolar cell: a pharmacological study in the tiger salamander." Journal of Neurophysiology 76, no. 3 (September 1, 1996): 2005–19. http://dx.doi.org/10.1152/jn.1996.76.3.2005.
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1. It is widely believed that signals contributing to the receptive field surrounds of retinal bipolar cells pass from horizontal cells to bipolar cells via GABAergic synapses. To test this notion, we applied gamma-aminobutyric acid (GABA) agonists and antagonists to isolated, perfused retinas of the salamander Ambystoma tigrinum while recording intracellularly from bipolar cells, horizontal cells, and photoreceptors. 2. As we previously reported, administration of the GABA analogue D-aminovaleric acid in concert with picrotoxin did not block horizontal cell responses or the center responses of bipolar cells but blocked the surround responses of both on-center and off-center bipolar cells. 3. Surround responses were not blocked by the GABA, antagonists picrotoxin or bicuculline, the GABAB agonist baclofen or the GABAB antagonist phaclofen, and the GABAC antagonists picrotoxin or cis-4-aminocrotonic acid. Combinations of these drugs were similarly ineffective. 4. GABA itself activated a powerful GABA uptake mechanism in horizontal cells for which nipecotic acid is a competitive agonist. It also activated, both in horizontal cells and bipolar cells, large GABAA conductances that shunted light responses but that could be blocked by picrotoxin or bicuculline. 5. GABA, administered together with picrotoxin to block the shunting effect of GABAA activation, did not eliminate bipolar cell surround responses at concentrations sufficient to saturate the known types of GABA receptors. 6. Surround responses were not blocked by glycine or its antagonist strychnine, or by combinations of drugs designed to eliminate GABAergic and glycinergic pathways simultaneously. 7. Although we cannot fully discount the involvement of a novel GABAergic synapse, the simplest explanation of our findings is that the primary pathway mediating the bipolar cell's surround is neither GABAergic nor glycinergic.
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Lukasiewicz, Peter D., and Rachel O. L. Wong. "GABAC receptors on ferret retinal bipolar cells: A diversity of subtypes in mammals?" Visual Neuroscience 14, no. 5 (September 1997): 989–94. http://dx.doi.org/10.1017/s095252380001169x.
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AbstractThe GABAC receptor subtypes on bipolar cells of rats and cold-blooded vertebrates differ in their pharmacological properties and probably have different molecular compositions. With the exception of the rat, native GABAC receptors in mammals had not been studied. In ferret, whole-cell, voltage-clamp recordings were made from bipolar cells in the retinal slice preparation to determine which subtype of GABAC receptor predominated. Puff-evoked GABA currents in bipolar cells were partially reduced by the GABAA receptor antagonist bicuculline, indicating that both GABAA and GABAC receptors mediated the responses. By contrast, GABA currents of ganglion cells were always completely blocked by bicuculline, indicating that GABAA receptors predominated on these cells. Small-amplitude GABA currents of bipolar cells evoked by short-duration puffs were less sensitive to bicuculline than large-amplitude currents evoked by long-duration puffs. This indicates that GABAc receptors mediated proportionately more of the small-amplitude, puff-evoked responses and GABAA receptors mediated more of the large-amplitude, puff-evoked responses. In bipolar cells, the bicuculline-resistant component of the GABA current was entirely blocked by 3-APMPA (3-aminopropyl-(methyl)phosphonic acid), a GABAC receptor antagonist. Picrotoxin, which is relatively ineffective at rat GABAC receptors, completely blocked GABA currents in ferret bipolar cells, indicating that GABAC receptors on ferret bipolar cells resemble those in lower vertebrates rather than those in the rat retina. These results suggest that there may be a diversity of GABAc receptor subtypes on mammalian bipolar cells.
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Ellefsen, Stian, Kåre-Olav Stensløkken, Cathrine E. Fagernes, Tom A. Kristensen, and Göran E. Nilsson. "Expression of genes involved in GABAergic neurotransmission in anoxic crucian carp brain (Carassius carassius)." Physiological Genomics 36, no. 2 (January 2009): 61–68. http://dx.doi.org/10.1152/physiolgenomics.90301.2008.
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The crucian carp, Carassius carassius, survives days to months without oxygen, depending on temperature. In the anoxic crucian carp brain, increased GABAergic inhibition, mediated by increased extracellular levels of GABA, has been shown to suppress electric activity and ATP consumption. To investigate an involvement of gene expression in this response, we utilized real-time RT-PCR to test the effect of 1 and 7 days anoxia (8°C) on the expression of 22 genes, including nine GABAA receptor subunits (α1–6, β2, δ, and γ2), three GABAB receptor subunits (GB1a-1b and GB2), three enzymes involved in GABA metabolism (GAD65 and GAD67, GABAT), four GABA transporters (GAT1, 2a-b and 3), two GABAA receptor-associated proteins (GABARAP 1 and 2), and the K+/Cl− cotransporter KCC2. While the expression of GABAA receptor subunits was dominated by α4-, α6-, and δ-subunits, all of which are located to extrasynaptic sites in mammalian brains and respond to elevations in extracellular levels of GABA by showing tonic activity patterns, the expression of GABA transporters was dominated by GAT2 (a and b) and GAT3, which also show extrasynaptic location in mammals. These expression patterns differ from those observed in mammals and may be a prerequisite for GABAergic inhibition of anoxic metabolic rate in crucian carp. Furthermore, while the expression of the majority of the genes was largely unaltered by anoxia, the expression of GAT2 and GAT3 decreased to 20%. This suggests impairment of GABA transport, which could be a mechanism behind the accumulation of extracellular GABA and the increased GABAergic inhibition.
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Athapaththu, Athapaththu Mudiyanselage Gihan Kavinda, Ilandarage Menu Neelaka Molagoda, Rajapaksha Gedara Prasad Tharanga Jayasooriya, Yung Hyun Choi, You-Jin Jeon, Joung-Hyun Park, Bae-Jin Lee, and Gi-Young Kim. "Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABAA and GABAB Receptors." International Journal of Molecular Sciences 22, no. 20 (October 19, 2021): 11254. http://dx.doi.org/10.3390/ijms222011254.
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Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM β-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM) -induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABAA and GABAB receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABAC receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABAA and GABAB receptors and leads to growth promotion performance via IGF-1R.
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Jensen, Kimmo, Chi-Sung Chiu, Irina Sokolova, Henry A. Lester, and Istvan Mody. "GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus." Journal of Neurophysiology 90, no. 4 (October 2003): 2690–701. http://dx.doi.org/10.1152/jn.00240.2003.
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After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.
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MÖLLER, ANNA, and THOR EYSTEINSSON. "Modulation of the components of the rat dark-adapted electroretinogram by the three subtypes of GABA receptors." Visual Neuroscience 20, no. 5 (September 2003): 535–42. http://dx.doi.org/10.1017/s0952523803205071.
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The separate components of the dark-adapted electroretinogram (ERG) are believed to reflect the electric activity of neurones in both the inner and the outer layers of the retina, although their precise origin still remains unclear. The purpose of this study was to examine whether selective blockage or stimulation of the different subtypes of GABA receptors might help further elucidate the cellular origin of the components of the dark-adapted ERG. The rat retina is of interest since the localization and physiology of GABA receptors in that retina have been examined in great detail. GABA agonists and antagonists, known to affect the responses of neurons in the inner plexiform layer, were injected into the vitreous of one eye while ERG responses evoked by flashes of white light were recorded. GABA and the GABAa agonist isoguvacine completely removed the oscillatory potentials (OPs) and reduced the amplitude of the a- and b-waves. TPMPA, a GABAc antagonist, reduced the a- and b-waves but had no significant effect on the OPs. Baclofen, a GABAb agonist, reduced the amplitude of the a- and b-waves, without having any effects on the amplitude of the OPs. The GABAb antagonist CGP35348 increased the amplitudes of the a- and b-wave without having an effect on the amplitudes of the OPs. The GABAb receptor ligands had significant and opposite effect on the latency of the OPs. These results indicate that retinal neurons, presumably a subpopulation of amacrine cells, that have GABAb receptors are not the source of the OPs of the ERG, although they may modulate these wavelets in some manner, while contributing to the generation of the dark-adapted a- and b-waves. OPs are modified by stimulation of GABAa receptors, and the a- and b-waves by stimulation of all GABA receptor subtypes.
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Massey, Stephen C., David M. Linn, Christopher A. Kittila, and Wajid Mirza. "Contributions of GABAA receptors and GABAC receptors to acetylcholine release and directional selectivity in the rabbit retina." Visual Neuroscience 14, no. 5 (September 1997): 939–48. http://dx.doi.org/10.1017/s0952523800011652.
Full textAbstract:
AbstractGABA is a major inhibitory neurotransmitter in the mammalian retina and it acts at many different sites via a variety of postsynaptic receptors. These include GABAA receptors and bicuculline-resistant GABAC receptors. The release of acetylcholine (ACh) is inhibited by GABA and strongly potentiated by GABA antagonists. In addition, GABA appears to mediate the null inhibition which is responsible for the mechanism of directional selectivity in certain ganglion cells. We have used these two well-known examples of GABA inhibition to compare three GABA antagonists and assess the contributions of GABAA and GABAC receptors. All three GABA antagonists stimulated ACh release by as much as ten-fold. By this measure, the ED50s for SR-95531, bicuculline, and picrotoxin were 0.8, 7.0, and 14 μM, respectively. Muscimol, a potent GABAA agonist, blocked the effects of SR-95531 and bicuculline, but not picrotoxin. This indicates that SR-95531 and bicuculline are competitive antagonists at the GABAA receptor, while picrotoxin blocks GABAA responses by acting at a different, nonreceptor site such as the chloride channel. In the presence of a saturating dose of SR-95531 to completely block GABAA receptors, picrotoxin caused a further increase in the release of ACh. This indicates that picrotoxin potentiates ACh release by a mechanism in addition to the block of GABAA responses, possibly by also blocking GABAC receptors, which have been associated with bipolar cells. All three GABA antagonists abolished directionally selective responses from ON/OFF directional-selective (DS) ganglion cells. In this system, the ED50s for SR-95531, bicuculline, and picrotoxin were 0.7 μM, 8 μM, and 94.6 μM, respectively. The results with SR-95531 and bicuculline indicate that GABAA receptors mediate the inhibition responsible for directional selectivity. The addition of picrotoxin to a high dose of SR-95531 caused no further increase in firing rate. The comparatively high dose required for picrotoxin also suggests that GABAC receptors do not contribute to directional selectivity. This in turn suggests that feedforward GABAA inhibition, as opposed to feedback at bipolar terminals, is responsible for the null inhibition underlying directional selectivity.
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Jiménez-Dinamarca, Ivanka, Rachel Reyes-Lizana, Yordan Lemunao-Inostroza, Kevin Cárdenas, Raimundo Castro-Lazo, Francisca Peña, Claudia M. Lucero, et al. "GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels." International Journal of Molecular Sciences 23, no. 21 (November 7, 2022): 13625. http://dx.doi.org/10.3390/ijms232113625.
Full textAbstract:
Gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.
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Pham, T. M., and J. C. Lacaille. "Multiple postsynaptic actions of GABA via GABAB receptors on CA1 pyramidal cells of rat hippocampal slices." Journal of Neurophysiology 76, no. 1 (July 1, 1996): 69–80. http://dx.doi.org/10.1152/jn.1996.76.1.69.
Full textAbstract:
1. The effects of gamma-aminobutyric acid (GABA) on non-GABAA receptors were investigated with intracellular recordings in CA1 pyramidal cells of rat hippocampal slices in the presence of antagonists of GABAA receptors (50 microM bicuculline and 50 microM picrotoxin), N-methyl-D-aspartate (NMDA) and non-NMDA receptors (100 microM 2-amino-5-phosphonopentanoic acid and 40 microM 6-cyano-7-nitroquinoxaline-2,3-dione, respectively), and of a blocker of GABA uptake (1 mM nipecotic acid). The effects of GABA were compared with those of the selective GABAB agonist (-)baclofen [CGP-11973A; (-)BAC]. 2. In the presence of these antagonists, micropressure application of GABA into stratum radiatum evoked hyperpolarizations with relatively fast peak latency (2 s) and decay (12 s). (-)BAC, in the absence of antagonists, hyperpolarized cells, but with a slower time course (peak latency 8 s, decay 78 s). The mean equilibrium potential (Erev) of responses to GABA (-94 mV; n = 11) was similar to that of (-)BAC (-87 mV; n = 8), suggesting that both responses were mediated by K+ conductances. 3. Bath applications of 1 mM Ba2+ partly antagonized GABA responses in a reversible manner. The mean amplitude of the Ba(2+)-resistant GABA response was 46% of control (n = 16, P < 0.05). In contrast, (-) BAC responses were completely abolished by Ba2+ (n = 15), and the effect was reversible. Thus both GABA and (-)BAC activate a common Ba(2+)-sensitive conductance, but GABA may also activate another Ba(2+)-resistant conductance. 4. The Ba(2+)-resistant GABA response had a similar time course to control GABA responses, but its Erev was more depolarized (-79 mV, n = 8, P < 0.05). 5. During recordings with electrodes containing KCl to reverse the Cl- gradient, although GABA responses were smaller in amplitude, their time course and Erev (-91 mV; n = 10) were similar to those recorded with potassium acetate electrodes. Thus Cl- conductances may not be involved in these non-GABAA responses elicited by GABA. 6. During recordings with electrodes containing CsCl to block outward K+ currents, hyperpolarizing GABA responses were not observed (n = 8). In these conditions, GABA elicited depolarizing responses with a faster time course (peak latency 1 s, decay 5 s) than the hyperpolarizing responses recorded with electrodes containing KCl. Thus GABA may produce hyperpolarizations by activating K+ conductances, but it may also produce an additional depolarzing response via other Cs(+)-insensitive conductances. 7. During recordings with electrodes containing LiCl to interfere with G protein activation, hyperpolarizing GABA responses were blocked and depolarizing responses were unmasked (n = 5). These depolarizing responses were generally similar to those recorded with electrodes containing CsCl. GABA responses were also reduced during recordings with electrodes containing the irreversible G protein activator guanosine-5'-O-(3-thiotriphosphate). Thus hyperpolarizing GABA responses may involve G protein activation, but the depolarizing responses may not. 8. Bath application of the selective GABAB antagonist CGP-35348 (1 mM) did not significantly reduce hyperpolarizing GABA responses (18% reduction in amplitude, n = 6, P > 0.05), but completely suppressed (-)BAC responses (n = 2). The more potent and selective GABAB antagonist CGP-55845A (5 microM) abolished all GABA responses (n = 7). Thus all non-GABAA responses elicited by GABA may be mediated by GABAB receptors. 9. In conclusion, GABA, in the presence of GABAA antagonists, may produce in CA1 pyramidal cells two distinct postsynaptic responses mediated via GABAB receptors and G protein activation: l) GABA [and (-)BAC] may activate a Ba(2+)-sensitive K+ conductance, and 2) GABA [but not (-)BAC] may also generate a Ba(2+)-insensitive K+ conductance. GABA may also generate other ionic changes, via GABAB receptors, resulting in depolarization of pyramidal cells.
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Kobayashi, Suguru, Ryota Matsuo, Hisayo Sadamoto, Satoshi Watanabe, and Etsuro Ito. "Excitatory effects of GABA on procerebrum neurons in a slug." Journal of Neurophysiology 108, no. 4 (August 15, 2012): 989–98. http://dx.doi.org/10.1152/jn.01137.2010.
Full textAbstract:
Classical neurotransmitters, such as glutamate and γ-aminobutyric acid (GABA), often have different actions on invertebrate neurons from those reported for vertebrate neurons. In the terrestrial mollusk Limax, glutamate was found to function as an inhibitory transmitter in the procerebrum (PC), but it has not yet been clarified how GABA acts in the PC. We thus examined what effects GABA exerts on PC neurons in the present study. For this purpose, we first applied GABA to isolated PC preparations and recorded postsynaptic currents and potentials in PC neurons. The GABA application reduced the amplitude of inhibitory postsynaptic currents and depolarization-induced outward currents recorded in nonbursting neurons and increased the number of spontaneous spikes of nonbursting neurons. However, direct GABA-induced currents were not observed in either bursting or nonbursting neurons. These results suggest a potential direct effect of GABA on outward currents resulting in enhanced excitability of PC neurons. Next, we measured the change in [Ca2+]i in cultured PC neurons by application of GABA. The GABA application increased spontaneous Ca2+ events in cultured neurons. These Ca2+ events were ascribable to the influx of extracellular Ca2+. We then confirmed the presence of GABA and GABA receptors in the PC. The GABA-like immunoreactivity was observed in the neuropil layers of the PC, and the mRNAs for both GABAA and GABAB receptors were expressed in the PC. In particular, GABAB receptor mRNA, rather than GABAA, was found to be more abundantly expressed in the PC. These results suggest that GABA functions as an excitatory modulator for PC neurons via mainly GABAB receptors.
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Roberts, Bradley M., Emanuel F. Lopes, and Stephanie J. Cragg. "Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling." Cells 10, no. 3 (March 23, 2021): 709. http://dx.doi.org/10.3390/cells10030709.
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Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.
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Negri, Sharon, Francesca Scolari, Mauro Vismara, Valentina Brunetti, Pawan Faris, Giulia Terribile, Giulio Sancini, Roberto Berra-Romani, and Francesco Moccia. "GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells." Cells 11, no. 23 (November 30, 2022): 3860. http://dx.doi.org/10.3390/cells11233860.
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Numerous studies recently showed that the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), can stimulate cerebral angiogenesis and promote neurovascular coupling by activating the ionotropic GABAA receptors on cerebrovascular endothelial cells, whereas the endothelial role of the metabotropic GABAB receptors is still unknown. Preliminary evidence showed that GABAA receptor stimulation can induce an increase in endothelial Ca2+ levels, but the underlying signaling pathway remains to be fully unraveled. In the present investigation, we found that GABA evoked a biphasic elevation in [Ca2+]i that was initiated by inositol-1,4,5-trisphosphate- and nicotinic acid adenine dinucleotide phosphate-dependent Ca2+ release from neutral and acidic Ca2+ stores, respectively, and sustained by store-operated Ca2+ entry. GABAA and GABAB receptors were both required to trigger the endothelial Ca2+ response. Unexpectedly, we found that the GABAA receptors signal in a flux-independent manner via the metabotropic GABAB receptors. Likewise, the full Ca2+ response to GABAB receptors requires functional GABAA receptors. This study, therefore, sheds novel light on the molecular mechanisms by which GABA controls endothelial signaling at the neurovascular unit.
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Krantis, Anthony. "GABA in the Mammalian Enteric Nervous System." Physiology 15, no. 6 (December 2000): 284–90. http://dx.doi.org/10.1152/physiologyonline.2000.15.6.284.
Full textAbstract:
γ-Aminobutyric acid (GABA) is a transmitter of enteric interneurons, targeting excitatory GABAA or inhibitory GABAB receptors that modulate motility and mucosal function. Enteric GABA may also subserve hormonal and paracrine signaling. Disruption in gastrointestinal function following perturbation of enteric GABA receptors presents potential new target sites for drug development.
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YANG, XIONG-LI, FAN GAO, and SAMUEL M. WU. "Modulation of horizontal cell function by GABAA and GABAC receptors in dark- and light-adapted tiger salamander retina." Visual Neuroscience 16, no. 5 (September 1999): 967–79. http://dx.doi.org/10.1017/s0952523899165167.
Full textAbstract:
The physiological function of GABA transporters and GABA receptors in retinal horizontal cells (HCs) under dark- and light-adapted conditions were studied by whole-cell voltage clamp and intracellular recording techniques in retinal slices and whole-mounted isolated retinas of the larval tiger salamander. Puff application of GABA in picrotoxin elicited a NO-711 (a potent GABA transporter blocker)-sensitive inward current that did not exhibit a reversal potential in the physiological range, consistent with the idea that these HCs contain electrogenic GABA transporters. Application of GABA in NO-711 elicited a chloride current in HCs; about half of the current was suppressed by bicuculline or I4AA (a GABAC receptor antagonist), and the remaining half was suppressed by bicuculline + I4AA or picrotoxin. In whole-mount retinas, NO-711, bicuculline, I4AA, or picrotoxin hyperpolarized the HCs and enhanced the light responses under dark-adapted conditions, and blocked the time-dependent recovery of HC membrane potential and light responses during background illumination. Based on the parallel conductance model, GABA released in darkness mediates a chloride conductance about three times greater than the leak conductance or the glutamate-gated cation conductance. About half of this chloride conductance is mediated by GABAA receptors, and the other half is mediated by GABAC receptors. These results suggest that GABA released from HCs through the NO-711-sensitive GABA transporters activates GABAA and GABAC receptors, resulting in chloride conductance increase which leads to a HC depolarization and reduction of the light response. Additionally, GABA transporters also mediate GABA release in background light that is responsible for the recovery of HC membrane potential and light responses.
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Kaneda, Katsuyuki, and Hitoshi Kita. "Synaptically Released GABA Activates Both Pre- and Postsynaptic GABAB Receptors in the Rat Globus Pallidus." Journal of Neurophysiology 94, no. 2 (August 2005): 1104–14. http://dx.doi.org/10.1152/jn.00255.2005.
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The globus pallidus (GP) contains abundant GABAergic synapses and GABAB receptors. To investigate whether synaptically released GABA can activate pre- and postsynaptic GABAB receptors in the GP, physiological recordings were performed using rat brain slice preparations. Cell-attached recordings from GABAA antagonist-treated preparations revealed that repetitive local stimulation induced a GABAB antagonist-sensitive pause in spontaneous firings of GP neurons. Whole cell recordings revealed that the repetitive stimulation evoked fast excitatory postsynaptic potentials followed by a slow inhibitory postsynaptic potential (IPSP) in GP neurons. The slow IPSP was insensitive to a GABAA receptor antagonist, increased in amplitude with the application of ionotropic glutamate receptor antagonists, and was suppressed by the GABAB antagonist CGP55845 . The reversal potential of the slow IPSP was close to the potassium equilibrium potential. These results suggest that synaptically released GABA activated postsynaptic GABAB receptors and induced the pause and the slow IPSP. On the other hand, in the neurons that were treated to block postsynaptic GABAB responses, CGP55845 increased the amplitudes of repetitive local stimulation-induced GABAA-mediated inhibitory postsynaptic currents (IPSCs) but not the ionotropic glutamate-mediated excitatory postsynaptic currents. Moreover, the GABAB receptor specific agonist baclofen reduced the frequency of miniature IPSCs without altering their amplitude distributions. These results suggest that synaptically released GABA also activated presynaptic GABAB autoreceptors, resulting in decreased GABA release in the GP. Together, we infer that both pre- and postsynaptic GABAB receptors may play crucial roles in the control of GP neuronal activity.
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Takeuchi, Kasumi. "GABA, A Primary Metabolite Controlled by the Gac/Rsm Regulatory Pathway, Favors a Planktonic Over a Biofilm Lifestyle in Pseudomonas protegens CHA0." Molecular Plant-Microbe Interactions® 31, no. 2 (February 2018): 274–82. http://dx.doi.org/10.1094/mpmi-05-17-0120-r.
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In Pseudomonas protegens CHA0 and other fluorescent pseudomonads, the Gac/Rsm signal transduction pathway is crucial for the expression of secondary metabolism and the biological control of fungi, nematodes, and insects. Based on the findings of a previous metabolomic study, the role of intracellular γ-aminobutyrate (GABA) as a potential signal in the Gac/Rsm pathway was investigated herein. The function and regulation of a gabDT (c01870-c01880) gene cluster in strain CHA0 were described. The gabT gene encoded GABA transaminase (GABAT) and enabled the growth of the bacterium on GABA, whereas the upstream gabD gene (annotated as a gene encoding succinic semialdehyde dehydrogenase) had an unknown function. A gacA mutant exhibited low GABAT activity, leading to the markedly greater intracellular accumulation of GABA than in the wild type. In the gacA mutant, the RsmA and RsmE proteins caused translational gabD repression, with concomitant gabT repression. Due to very low GABAT activity, the gabT mutant accumulated GABA to high levels. This trait promoted a planktonic lifestyle, reduced biofilm formation, and favored root colonization without exhibiting the highly pleiotropic gacA phenotypes. These results suggest an important role of GABA in the Gac/Rsm-regulated niche adaptation of strain CHA0 to plant roots.
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Wagner, Ashley, Zhimin Yan, and Marianna Kulka. "A Human Microglial Cell Line Expresses γ-Aminobutyric Acid (GABA) Receptors and Responds to GABA and Muscimol by Increasing Production of IL-8." Neuroglia 4, no. 3 (June 28, 2023): 172–87. http://dx.doi.org/10.3390/neuroglia4030012.
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Gamma-aminobutyric acid (GABA) is an essential neurotransmitter and an important regulator of neuroinflammation and disease. Microglia are important immune cells in the brain that express GABA receptors (GABAR) and respond to both GABA and GABAR agonists, yet the effect of GABA on microglial inflammatory responses is unclear. We hypothesized that GABA and GABAR agonists might modify the activation of a human microglial cell line (HMC3). We further hypothesized that Amanita muscaria extract (AME-1), which contained GABAR agonists (GABA and muscimol), would similarly stimulate HMC3. Ligand-gated GABAR (GABAAR) and G protein-coupled GABAR (GABABR) subunit expression was analyzed by qRT-PCR, metabolic activity was determined by nicotinamide adenine dinucleotide (NADH)-dependent oxidoreductase assay (XTT), reactive oxygen species (ROS) generation was analyzed by 2′,7′-dichlorodihydrofluorescein diacetate (DCFDA), and interleukin-8 (IL-8) production was analyzed by an enzyme-linked immunosorbent assay (ELISA). HMC3 expressed several neuroreceptors such as subunits of the GABAA receptor (GABAAR). HMC3 constitutively produce IL-8 and ROS. Both muscimol and GABA stimulated HMC3 to produce more IL-8 but had no effect on constitutive ROS production. GABA and muscimol altered the morphology and Iba1 localization of HMC3. GABA, but not muscimol, increased HMC3 metabolic activity. Similarly, AME-1 induced HMC3 to produce more IL-8 but not ROS and altered cell morphology and Iba1 localization. GABA induction of IL-8 was blocked by bicuculline, an antagonist of GABAAR. AME-1-induced production of IL-8 was not blocked by bicuculline, suggesting that AME-1’s effect on HMC3 was independent of GABAAR. In conclusion, these data show that GABA and GABA agonists stimulate HMC3 to increase their production of IL-8. Mixtures that contain GABA and muscimol, such as AME-1, have similar effects on HMC3 that are independent of GABAAR.
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Molagoda, Ilandarage Menu Neelaka, Mirissa Hewage Dumindu Kavinda, Hyung Won Ryu, Yung Hyun Choi, Jin-Woo Jeong, Sanghyuck Kang, and Gi-Young Kim. "Gamma-Aminobutyric Acid (GABA) Inhibits α-Melanocyte-Stimulating Hormone-Induced Melanogenesis through GABAA and GABAB Receptors." International Journal of Molecular Sciences 22, no. 15 (July 31, 2021): 8257. http://dx.doi.org/10.3390/ijms22158257.
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Gamma-aminobutyric acid (GABA) is considered the primary inhibitory neurotransmitter in the human cortex. However, whether GABA regulates melanogenesis has not been comprehensively elucidated. In this study, we reveal that GABA (20 mM) significantly inhibited α-melanocyte-stimulating hormone (α-MSH)-induced extracellular (from 354.9% ± 28.4% to 126.5% ± 16.0%) and intracellular melanin contents (from 236.7% ± 11.1% to 102.7% ± 23.1%) in B16F10 melanoma cells, without inducing cytotoxicity. In addition, α-MSH-induced hyperpigmentation in zebrafish larvae was inhibited from 246.3% ± 5.4% to 116.3% ± 3.1% at 40 mM GABA, displaying no apparent cardiotoxicity. We also clarify that the GABA-mediated antimelanogenic properties were related to the direct inhibition of microphthalmia-associated transcription factor (MITF) and tyrosinase expression by inhibiting cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Furthermore, under α-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABAA and GABAB receptors, with subsequent inhibition of Ca2+ accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABAA receptor antagonist, and CGP 46381, a GABAB receptor antagonist, reversed the antimelanogenic effect of GABA following α-MSH treatment by upregulating Ca2+ accumulation. In conclusion, our results indicate that GABA inhibits α-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.
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Fergus, Andrea, and Kevin S. Lee. "GABAergic Regulation of Cerebral Microvascular Tone in the Rat." Journal of Cerebral Blood Flow & Metabolism 17, no. 9 (September 1997): 992–1003. http://dx.doi.org/10.1097/00004647-199709000-00009.
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The role of GABA in regulating cerebral microvessels was examined in the parenchyma of the hippocampus and the surface of the neocortex. Microvessels were monitored in in vitro slices using computer-assisted videomicroscopy, and synaptically evoked field responses were simultaneously recorded. γ-Aminobutyric acid (GABA) and the GABAA receptor agonist, muscimol, elicited vasodilation in hippocampal microvessels, whereas the GABAB receptor agonist, baclofen, elicited constriction. The muscimol-induced dilation persisted in the presence of the nitric oxide synthase inhibitor, N-nitro-l-arginine, indicating that this response is not mediated by nitric oxide. Inhibition of neuronal discharge activity with tetrodotoxin did not alter this dilation, but it fully blocked the constrictor response to baclofen. These data suggest that GABAB-mediated, but not GABAA-mediated, responses are dependent on action potential generation. The GABAA receptor antagonists, bicuculline and picrotoxin, elicited constriction, suggesting a tonic dilatory influence by endogenous GABA. Bicuculline-induced constriction was not attenuated by tetrodotoxin. In contrast, these vessels were unresponsive to the GABAB receptor antagonist, 2-hydroxysaclofen. Hippocampal microvessels dilated in response to moderate hypoxia, and this response persisted in the presence of bicuculline, indicating that the hypoxia-induced dilation is not mediated by an action at GABAA receptors. In arterioles located on the surface of the neocortex (i.e., not embedded in the parenchyma of the brain), muscimol elicited vasodilation, whereas bicuculline was ineffective. These results suggest that although these vessels are responsive to GABA, the local concentration of endogenous GABA is insufficient to elicit a tonic effect at rest. These findings raise the possibility that GABA plays a role in local neurovascular signaling in the parenchyma of the brain.
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Roberts, D. J., W. L. Hasler, and C. Owyang. "GABA mediation of the dual effects of somatostatin on guinea pig ileal myenteric cholinergic transmission." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 5 (May 1, 1993): G953—G960. http://dx.doi.org/10.1152/ajpgi.1993.264.5.g953.
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Somatostatin (SS) has both excitatory and inhibitory actions on myenteric cholinergic transmission, which are mimicked by gamma-aminobutyric acid (GABA). We hypothesized that both effects of SS are mediated by neural GABA pathways. In guinea pig ileal longitudinal muscle-myenteric plexus, SS evoked [3H]-GABA release verifying GABA neural activation. SS (10(-9)-10(-5) M) stimulation of atropine-sensitive ileal contraction and evocation of tetrodotoxin-sensitive [3H]acetylcholine (ACh) release was mimicked by the GABAA agonist muscimol but not the GABAB agonist baclofen. SS (10(-7) M)-evoked contraction and [3H]ACh release were markedly reduced by the GABAA antagonist bicuculline (10(-5) M) but not the GABAB antagonist phaclofen. Cholecystokinin (CCK) evokes ileal contraction via an atropine-sensitive pathway and stimulates ACh release via adenylate cyclase activation. SS inhibited contraction and release evoked by CCK (10(-7) M). These inhibitory actions were reversed by phaclofen but not bicuculline and were mimicked by baclofen but not muscimol. Pertussis toxin (200 ng/ml for 3 h) reversed the inhibitory effects of SS and baclofen on CCK-stimulated contraction and release. In conclusion, SS modulates ileal cholinergic pathways by stimulation of GABA neural pathways. The excitatory action of SS is mediated by GABAA receptors, whereas the inhibitory action utilizes GABAB receptors via a pertussis toxin-sensitive G protein.
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Trudeau, V. L., B. D. Sloley, and R. E. Peter. "GABA stimulation of gonadotropin-II release in goldfish: involvement of GABAA receptors, dopamine, and sex steroids." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 265, no. 2 (August 1, 1993): R348—R355. http://dx.doi.org/10.1152/ajpregu.1993.265.2.r348.
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The involvement of gamma-aminobutyric acid (GABA) in regulation of pituitary gonadotropin-II (GTH-II) release was studied in the goldfish. Intraperitoneal injection of GABA (300 micrograms/g) stimulated an increase in serum GTH-II levels at 30 min postinjection. The GABAA receptor agonist muscimol (0.1-10 micrograms/g) stimulated GTH-II in a dose-dependent manner. Baclofen, a GABAB receptor agonist, had a small but significant stimulatory effect at 1 and 10 micrograms/g; the amount of GTH-II released in response to baclofen was significantly less (P < 0.05) than that released by muscimol. Pretreatment of goldfish with bicuculline, a GABAA receptor antagonist, but not saclofen, a GABAB receptor antagonist, blocked the stimulatory effect of GABA on serum GTH-II. Elevation of brain and pituitary GABA levels with the GABA transaminase inhibitor, gamma-vinyl-GABA (GVG), decreased hypothalamic and pituitary dopamine (DA) turnover rates, indicating that GABA may stimulate GTH-II release in the goldfish by decreasing dopaminergic inhibition of GTH-II release. The release of GTH-II stimulated by muscimol and GVG was potentiated by pharmacological agents that decrease inhibitory dopaminergic tone, indicating that DA may also inhibit GABA-stimulated GTH-II release. Based on the linear 24-h accumulation of GABA in brain and pituitary after GVG injection, implantation of testosterone, estradiol, or progesterone, previously shown to regulate the serum GTH-II release response to gonadotropin-releasing hormone and GABA, was also found to modulate GABA synthesis in the brain and pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)
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Grider, J. R., and G. M. Makhlouf. "Enteric GABA: mode of action and role in the regulation of the peristaltic reflex." American Journal of Physiology-Gastrointestinal and Liver Physiology 262, no. 4 (April 1, 1992): G690—G694. http://dx.doi.org/10.1152/ajpgi.1992.262.4.g690.
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The mode of action of gamma-aminobutyric acid (GABA) and the role of myenteric GABA neurons in the regulation of peristalsis were examined in various preparations of rat colonic muscle. GABA had no contractile, relaxant, or modulatory effect on smooth muscle cells isolated from the circular muscle layer. In innervated circular muscle strips, GABA elicited concentration-dependent relaxation accompanied by release of vasoactive intestinal peptide (VIP). Relaxation and VIP release were inhibited by tetrodotoxin and by the GABAA receptor antagonist bicuculline but not by the GABAB receptor antagonist phaclofen. Relaxation was inhibited by the VIP receptor antagonist VIP-(10-28) implying that VIP release was coupled to muscle relaxation. Relaxation was augmented by atropine implying that GABA also activated cholinergic neurons causing release of acetylcholine that attenuated the relaxant response. This pharmacological profile was evident when GABA was released from intrinsic GABA neurons during peristalsis induced by radial stretch. Blockade of GABAA receptors with bicuculline inhibited the descending relaxation mediated by VIP motor neurons and the ascending contraction mediated by cholinergic motor neurons. Stimulation of these receptors with exogenous GABA had the opposite effect. We conclude that on release from myenteric neurons, GABA acts via GABAA receptors on cholinergic and VIP motor neurons responsible for the two components of the peristaltic reflex.
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Bogusz, Adrienne L., Steven L. Hardy, Michael N. Lehman, John M. Connors, Stanley M. Hileman, Joanna H. Sliwowska, Heather J. Billings, et al. "Evidence that γ-Aminobutyric Acid Is Part of the Neural Circuit Mediating Estradiol Negative Feedback in Anestrous Ewes." Endocrinology 149, no. 6 (March 6, 2008): 2762–72. http://dx.doi.org/10.1210/en.2007-1362.
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Seasonal anestrus in ewes is driven by an increase in response to estradiol (E2) negative feedback. Compelling evidence indicates that inhibitory A15 dopaminergic (DA) neurons mediate the increased inhibitory actions of E2 in anestrus, but these neurons do not contain estrogen receptors. Therefore, we have proposed that estrogen-responsive afferents to A15 neurons are part of the neural circuit mediating E2 negative feedback in anestrus. This study examined the possible role of afferents containing γ-aminobutyric acid (GABA) and nitric oxide (NO) in modulating the activity of A15 neurons. Local administration of NO synthase inhibitors to the A15 had no effect on LH, but GABA receptor ligands produced dramatic changes. Administration of either a GABAA or GABAB receptor agonist to the A15 increased LH secretion in ovary-intact ewes, suggesting that GABA inhibits A15 neural activity. In ovariectomized anestrous ewes, the same doses of GABA receptor agonist had no effect, but combined administration of a GABAA and GABAB receptor antagonist to the A15 inhibited LH secretion. These data are consistent with the hypothesis that endogenous GABA release within the A15 is low in ovary-intact anestrous ewes and elevated after ovariectomy. Using dual immunocytochemistry, we observed that GABAergic varicosities make close contacts on to A15 neurons and that A15 neurons contain both the GABAA-α1 and the GABAB-R1 receptor subunits. Based on these data, we propose that in anestrous ewes, E2 inhibits release of GABA from afferents to A15 DA neurons, increasing the activity of these DA neurons and thus suppressing episodic secretion of GnRH and LH.
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Bennett, Ben D., John R. Huguenard, and David A. Prince. "Adrenoceptor-Mediated Elevation of Ambient GABA Levels Activates Presynaptic GABAB Receptors in Rat Sensorimotor Cortex." Journal of Neurophysiology 78, no. 1 (July 1, 1997): 561–66. http://dx.doi.org/10.1152/jn.1997.78.1.561.
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Bennett, Ben D., John R. Huguenard, and David A. Prince. Adrenoceptor-mediated elevation of ambient GABA levels activates presynaptic GABAB receptors in rat sensorimotor cortex. J. Neurophysiol. 78: 561–566, 1997. At inhibitory synapses in the mature neocortex and hippocampus in vitro, spontaneous action-potential-dependent and -independent release of γ-aminobutyric acid (GABA) activates postsynaptic GABAA receptors but not pre- or postsynaptic GABAB receptors. Elevation of synaptic GABA levels with pharmacological agents or electrical stimulation can cause activation of GABAB receptors, but the physiological conditions under which such activation occurs need further elucidation. In rodent sensorimotor cortex, epinephrine produced a depression in the amplitude of evoked monosynaptic inhibitory postsynaptic currents (IPSCs) and a concomitant, adrenoceptor-mediated increase in the frequency of spontaneous IPSCs. Blockade of GABAB receptors prevented the depression of evoked IPSC amplitude by epinephrine but did not affect the increase in spontaneous IPSC frequency. These data show that adrenoceptor-mediated increases in spontaneous IPSCs can cause activation of presynaptic GABAB receptors and indirectly modulate impulse-related GABA release, presumably through elevation of synaptic GABA levels.
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Obrietan, Karl, and Anthony N. van den Pol. "GABAB Receptor-Mediated Inhibition of GABAA Receptor Calcium Elevations in Developing Hypothalamic Neurons." Journal of Neurophysiology 79, no. 3 (March 1, 1998): 1360–70. http://dx.doi.org/10.1152/jn.1998.79.3.1360.
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Obrietan, K. and Anthony N. van den Pol. GABAB receptor-mediated inhibition of GABAA receptor calcium elevations in developing hypothalamic neurons. J. Neurophysiol. 79: 1360–1370, 1998. In the CNS, γ-aminobutyric acid (GABA) affects neuronal activity through both the ligand-gated GABAA receptor channel and the G protein-coupled GABAB receptor. In the mature nervous system, both receptor subtypes decrease neural excitability, whereas in most neurons during development, the GABAA receptor increases neural excitability and raises cytosolic Ca2+ levels. We used Ca2+ digital imaging to test the hypothesis that GABAA receptor-mediated Ca2+ rises were regulated by GABAB receptor activation. In young, embryonic day 18, hypothalamic neurons cultured for 5 ± 2 days in vitro, we found that cytosolic Ca2+ rises triggered by synaptically activated GABAA receptors were dramatically depressed (>80%) in a dose-dependent manner by application of the GABAB receptor agonist baclofen (100 nM–100 μM). Coadministration of the GABAB receptor antagonist 2-hydroxy-saclofen or CGP 35348 reduced the inhibitory action of baclofen. Administration of the GABAB antagonist alone elicited a reproducible Ca2+ rise in >25% of all synaptically active neurons, suggesting that synaptic GABA release exerts a tonic inhibitory tone on GABAA receptor-mediated Ca2+ rises via GABAB receptor activation. In the presence of tetrodotoxin the GABAA receptor agonist muscimol elicited robust postsynaptic Ca2+ rises that were depressed by baclofen coadministration. Baclofen-mediated depression of muscimol-evoked Ca2+ rises were observed in both the cell bodies and neurites of hypothalamic neurons taken at embryonic day 15 and cultured for three days, suggesting that GABAB receptors are functionally active at an early stage of neuronal development. Ca2+ rises elicited by electrically induced synaptic release of GABA were largely inhibited (>86%) by baclofen. These results indicate that GABAB receptor activation depresses GABAA receptor-mediated Ca2+ rises by both reducing the synaptic release of GABA and decreasing the postsynaptic Ca2+ responsiveness. Collectively, these data suggest that GABAB receptors play an important inhibitory role regulating Ca2+ rises elicited by GABAA receptor activation. Changes in cytosolic Ca2+ during early neural development would, in turn, profoundly affect a wide array of physiological processes, such as gene expression, neurite outgrowth, transmitter release, and synaptogenesis.
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ROTOLO, THOMAS C., and RAMON F. DACHEUX. "Evidence for glycine, GABAA, and GABAB receptors on rabbit OFF-alpha ganglion cells." Visual Neuroscience 20, no. 3 (May 2003): 285–96. http://dx.doi.org/10.1017/s0952523803203072.
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Inhibitory synaptic transmission via GABA and glycine receptors plays a crucial role in shaping the excitatory response of neurons in the retina. Whole-cell recordings were obtained from ganglion cells in the intact rabbit eyecup preparation to correlate GABA- and glycine-activated currents with the presence of their specific receptors on morphologically identified α ganglion cells. Alpha ganglion cells were chosen based upon their large somata when viewing the retinal surface, and responses to light and dark spots were used to identify OFF-alpha ganglion cells. Light responses were abolished by superfusion of Ringer's containing cobalt to synaptically isolate the cell by blocking all Ca2+-mediated transmitter release. Pressure pulses of GABA and glycine were delivered to an area that encompassed the dendritic field while receptor antagonists were applied through superfusion to characterize the direct inhibition onto the ganglion cell. Physiological results indicated that OFF-α cells did not have any GABAC receptor-activated currents, but did express currents mediated by ionotropic GABAA receptors and metabotropic GABAB receptors that were blocked by their specific antagonists bicuculline and CGP55845, respectively. The amplitudes of strychnine-sensitive glycine-activated currents were always larger than the currents elicited by GABA. Confocal optical sections of physiologically identified, sulforhodamine B-stained cells displayed the localization of glycine and GABAA receptor subunit labeling dispersed over the stained dendrites.
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Zhang, S. J., and M. B. Jackson. "Properties of the GABAA receptor of rat posterior pituitary nerve terminals." Journal of Neurophysiology 73, no. 3 (March 1, 1995): 1135–44. http://dx.doi.org/10.1152/jn.1995.73.3.1135.
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1. We investigated gamma-aminobutyric acid (GABA) receptors using thin slice patch-clamp techniques in the swellings along axons of posterior pituitary nerve terminals. 2. Activation of the nerve terminal GABAA receptor induced a mean conductance change of 1.5 nS. Normalizing to area gave a mean conductance density of 0.38 mS/cm2. 3. Whereas GABAA receptor-mediated responses could be seen in 91% of the nerve terminals tested, GABAB receptor-mediated responses could not be detected. The GABAB receptor agonist baclofen had no effect on holding current or on voltage-activated K+ and Ca2+ channels. It is unlikely that nerve terminals of the posterior pituitary contain GABAB receptors. 4. The channel gated by the nerve terminal GABAA receptor exhibited only a single open conductance level. Only fully open and fully closed states were observed. Subconductance states typical of other GABAA receptor channels were not seen in the GABA-gated channels of posterior pituitary nerve terminals. 5. Both open time and closed time distributions were biexponential, indicating at least two open and two closed conformations of the channel. At a higher GABA concentration, long-duration openings predominated, suggesting that long-duration openings were distinguished from short-duration openings by the occupation of a greater number of agonist binding sites. 6. Sustained application of GABA desensitized the receptor with simple exponential kinetics. The time constant for desensitization was approximately 9 s for both GABA and muscimol. 7. Zinc ions at concentrations of 100 microM reduced GABA responses by only 22%. This weak sensitivity to zinc, together with a previous observation of benzodiazepine sensitivity, suggested that the nerve terminal GABAA receptor possesses a gamma-subunit. 8. Responses mediated by the GABAA receptor persist in whole terminal recordings without Mg-ATP in the pipette solution. Thus, in contrast to many other GABAA receptors, this receptor showed no rundown in the absence of ATP. 9. The GABAA receptor channel of posterior pituitary nerve terminals has many properties in common with GABAA receptors of other preparations. A number of subtle differences between the nerve terminal receptor described here and cell body receptors described elsewhere may reflect the presence of receptor protein subunits unique to nerve terminals.
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Osawa, Yoko, Dingbang Xu, David Sternberg, Joshua R. Sonett, Jeanine D’Armiento, Reynold A. Panettieri, and Charles W. Emala. "Functional expression of the GABAB receptor in human airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 5 (November 2006): L923—L931. http://dx.doi.org/10.1152/ajplung.00185.2006.
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γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABAA/GABAC) and metabotropic (GABAB) receptors (R). In addition to their location on neurons, GABA and functional GABAB receptors have been detected in nonneuronal cells in peripheral tissue. Although the GABABR has been shown to function as a prejunctional inhibitory receptor on parasympathetic nerves in the lung, the expression and functional coupling of GABAB receptors to Gi in airway smooth muscle itself have never been described. We detected the mRNA encoding multiple-splice variants of the GABABR1 and GABABR2 in total RNA isolated from native human and guinea pig airway smooth muscle and from RNA isolated from cultured human airway smooth muscle (HASM) cells. Immunoblots identified the GABABR1 and GABABR2 proteins in human native and cultured airway smooth muscle. The GABABR1 protein was immunohistochemically localized to airway smooth muscle in guinea pig tracheal rings. Baclofen, a GABABR agonist, elicited a concentration-dependent stimulation of [35S]GTPγS binding in HASM homogenates that was abrogated by the GABABR antagonist CGP-35348. Baclofen also inhibited adenylyl cyclase activity and induced ERK phosphorylation in HASM. Another GABABR agonist, SKF-97541, mimicked while pertussis toxin blocked baclofen’s effect on ERK phosphorylation, implicating Gi protein coupling. Functional GABAB receptors are expressed in HASM. GABA may modulate an uncharacterized signaling cascade via GABAB receptors coupled to the Gi protein in airway smooth muscle.
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Schmitt, David E., Russell H. Hill, and Sten Grillner. "The Spinal GABAergic System Is a Strong Modulator of Burst Frequency in the Lamprey Locomotor Network." Journal of Neurophysiology 92, no. 4 (October 2004): 2357–67. http://dx.doi.org/10.1152/jn.00233.2004.
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The spinal network coordinating locomotion is comprised of a core of glutamate and glycine interneurons. This network is modulated by several transmitter systems including spinal GABA interneurons. The purpose of this study is to explore the contribution of GABAergic neurons to the regulation of locomotor burst frequency in the lamprey model. Using gabazine, a competitive GABAA antagonist more specific than bicuculline, the goal was to provide a detailed analysis of the influence of an endogenous activation of GABAA receptors on fictive locomotion, as well as their possible interaction with GABAB and involvement of GABAC receptors. During N-methyl-d-aspartate (NMDA)-induced fictive locomotion (ventral root recordings in the isolated spinal cord), gabazine (0.1–100 μM) significantly increased the burst rate up to twofold, without changes in regularity or “burst quality.” Gabazine had a proportionately greater effect at higher initial burst rates. Picrotoxin (1–7.5 μM), a less selective GABAA antagonist, also produced a pronounced increase in frequency, but at higher concentrations, the rhythm deteriorated, likely due to the unspecific effects on glycine receptors. The selective GABAB antagonist CGP55845 also increased the frequency, and this effect was markedly enhanced when combined with the GABAA antagonist gabazine. The GABAC antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) had no effect on locomotor bursting. Thus the spinal GABA system does play a prominent role in burst frequency regulation in that it reduces the burst frequency by ≤50%, presumably due to presynaptic and soma-dendritic effects documented previously. It is not required for burst generation, but acts as a powerful modulator.
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Lummis, Sarah C. R. "Locating GABA in GABA receptor binding sites." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1343–46. http://dx.doi.org/10.1042/bst0371343.
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The Cys-loop family of ligand-gated ion channels contains both vertebrate and invertebrate members that are activated by GABA (γ-aminobutyric acid). Many of the residues that are critical for ligand binding have been identified in vertebrate GABAA and GABAC receptors, and specific interactions between GABA and some of these residues have been determined. In the present paper, I show how a cation–π interaction for one of the binding site residues has allowed the production of models of GABA docked into the binding site, and these orientations are supported by mutagenesis and functional data. Surprisingly, however, the residue that forms the cation–π interaction is not conserved, suggesting that GABA occupies subtly different locations even in such closely related receptors.
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Qian, Haohua, Lihong Li, Richard L. Chappell, and Harris Ripps. "GABA Receptors of Bipolar Cells From the Skate Retina: Actions of Zinc on GABA-Mediated Membrane Currents." Journal of Neurophysiology 78, no. 5 (November 1, 1997): 2402–12. http://dx.doi.org/10.1152/jn.1997.78.5.2402.
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Qian, Haohua, Lihong Li, Richard L. Chappell, and Harris Ripps. GABA receptors of bipolar cells from the skate retina: actions of zinc on GABA-mediated membrane currents. J. Neurophysiol. 78: 2402–2412, 1997. γ-Aminobutyric acid (GABA)–induced currents were recorded from isolated bipolar cells of the skate retina using perforated patch-clamp methodology. Pharmacological analysis of the responses, using selective agonists and antagonists of the major classes of GABA receptor, revealed the presence of both GABAA and GABAC receptors at both the dendrites and axon terminals of the bipolar cells. The two receptor types showed very different reactions to zinc, a divalent metallic cation that was detected in the synaptic terminal region of skate photoreceptors. Currents mediated by the activation of GABAC receptors were down-regulated by zinc, a feature that is typical of the action of zinc on GABAC receptors. On the other hand, the effects of zinc on GABAA receptor–mediated activity was highly dependent on zinc concentration. Unlike theGABAA receptors on other neurons, responses mediated by activation of the GABAA receptor of skate bipolar cells were significantly enhanced by zinc concentrations in the range of 0.1–100 μM; at higher concentrations of zinc (>100 μM), response amplitudes were suppressed below control levels. The enhancement of GABAA receptor activity on skate bipolar cells showed little voltage dependence, suggesting that zinc is acting on the extracellular domain of the GABAA receptor. In the presence of 10 μM zinc, the dose-response curve for 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; a GABAA agonist that suppresses GABAC-activated currents) was shifted to the left of the curve obtained in the absence of zinc, but without a significant change in the response maximum. This finding indicates that the enhancing effect of zinc is due primarily to its ability to increase the sensitivity of the GABAA receptor. The novel enhancement of neuronal GABAA receptor activity by zinc, observed previously in the GABAA-mediated responses of skate Müller (glial) cells, may reflect the presence of a unique subtype of GABAA receptor on the bipolar and Müller cells of the skate retina.
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Perkins, K. L., and R. K. Wong. "Ionic basis of the postsynaptic depolarizing GABA response in hippocampal pyramidal cells." Journal of Neurophysiology 76, no. 6 (December 1, 1996): 3886–94. http://dx.doi.org/10.1152/jn.1996.76.6.3886.
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1. Whole cell voltage-clamp recording with recording pipette solutions of differing ionic composition was used to determine the ionic basis of the depolarizing gamma-aminobutyric acid (GABA) response. In the presence of 4-aminopyridine and excitatory amino acid receptor blockers, giant GABA-mediated postsynaptic currents (GPSCs) were recorded from CA3 pyramidal neurons in hippocampal slices from adult guinea pigs. With the GABAB component blocked, the GPSC was composed of an initial outward current (GABAA component) that peaked at 115 ms followed by a late inward current (GABAD component) that peaked at 400-600 ms. 2. Reduction of the intracellular concentration of potassium ([K+]i)resulted in no significant change in the reversal potential of the GABAD component of the GPSC, indicating that it is not a nonspecific cation current. 3. The HCO3- permeability of the channel mediating the GABAD response was assessed by using recording pipette solutions containing three different concentrations of bicarbonate ([HCO3-], 19, 49, and 102 mM). The reversal potential of the GABAD response shifted in the depolarizing direction as the HCO3- equilibrium potential was shifted in the depolarizing direction, indicating that the channel mediating the GABAD response is permeable to HCO3-. The reversal potential of the GABAD response was more sensitive to changes in recording pipette [HCO3-] than the reversal potential of the GABAA response, indicating that the GABAD response is carried by HCO3- to a greater extent than the GABAA response. 4. The outward current-inward current sequence of the biphasic GPSC was reversed to an inward current-outward current sequence by using a high [Cl-]/low [HCO3-] recording pipette solution (40 mM Cl-/6 mM HCO3-), indicating that the GABAA component is more sensitive to changes in [Cl-]i, and the GABAD component is more sensitive to changes in [HCO3-]i. 5. These data indicate that the GABAD component of the GPSC is predominantly carried by HCO3-. While this result supports the recently propsed chloride accumulation model, the model in its present form cannot explain the inward current-outward current polarity sequence of the GPSC recorded with the high [Cl-]/low [HCO3-] intracellular solution. The data obtained using that solution reveal the need for a more expansive chloride accumulation/ depletion model or for a model utilizing two distinct ionotropic GABA channels with different anion permeability ratios to account for the biphasic nature of the GPSC.
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BENSON, JACK A. "A Novel Gaba Receptor in the Heart of a Primitive Arthropod, Limulus Polyphemus." Journal of Experimental Biology 147, no. 1 (November 1, 1989): 421–38. http://dx.doi.org/10.1242/jeb.147.1.421.
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1. The isolated, intact heart of the marine arachnid Limulus polyphemus continues to beat in vitro for many hours. Application of γaminobutyric acid (GABA) decreased the heart beat frequency with a threshold of 3xlO−7 moll−1 and an EC50 of 2.0±0.6xlO−5 moll−1 (mean±s.D., N = 8). At lO−4moll−1 and above the heart beat was completely and reversibly inhibited. 2. The agonist potency profile of the Limulus heart chronotropic GABA receptor was very similar to that of the vertebrate GABAA receptor: muscimol > ZAPA>GABA=⋍TACA>isoguvacine>THIP>3-aminopropane sulphonic acid> imidazole-4-acetic acid ⋍ß-guanidino proprionic acid ⋍5-aminovalerate. In contrast, the antagonist profile differed dramatically: bicuculline, pitrazepin and SR 95103, as well as the channel blocker picrotoxin, were without effect at concentrations up to 10−4moll−1. 3. The benzodiazepines clorazepate, flunitrazepam, flurazepam and diazepam, as well as the barbiturate sodium pentobarbital, were without effect on the GABA response, suggesting that the Limulus heart GABA receptor is not complexed with the benzodiazepine and barbiturate modulatory subunits that characterize vertebrate GABAA receptor. 4. The GABAB ligands baclofen, phaclophen and kojic amine were inactive on the heart. However, 3-aminopropyl-phosphonous acid (CGA147 823), a potent and highly selective GABAb agonist, was the most active of the compounds tested. It inhibited the heart beat with a threshold of about SnmolP1, an EC50 of 4.0±2.7×10−7 mol1−1, and produced total inhibition of the heart at 10−5moll−1. CGA 147 823 was inactive on the locust thoracic somal GABA receptors. 5. cis-4-aminocrotonic acid (CACA), the ligand defining a proposed GAB Actype receptor, was inactive on the heart. 6. The GABA-induced inhibition of the heart beat was enhanced by pretreatment with the GABA uptake inhibitor nipecotic acid but not with sodium valproate or ß-alanine. 7. The Limulus heart chronotropic GABA receptor appears to be of a hitherto undescribed type that differs in pharmacology from the vertebrate GABAA and GABAB receptors as well as from the well-defined GABA receptors on the somata of locust neurones and the muscle fibres of insects and the nematode Ascaris.
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Moore-Dotson, Johnnie M., Justin S. Klein, Reece E. Mazade, and Erika D. Eggers. "Different types of retinal inhibition have distinct neurotransmitter release properties." Journal of Neurophysiology 113, no. 7 (April 2015): 2078–90. http://dx.doi.org/10.1152/jn.00447.2014.
Full textAbstract:
Neurotransmitter release varies between neurons due to differences in presynaptic mechanisms such as Ca2+ sensitivity and timing. Retinal rod bipolar cells respond to brief dim illumination with prolonged glutamate release that is tuned by the differential release of GABA and glycine from amacrine cells in the inner retina. To test if differences among types of GABA and glycine release are due to inherent amacrine cell release properties, we directly activated amacrine cell neurotransmitter release by electrical stimulation. We found that the timing of electrically evoked inhibitory currents was inherently slow and that the timecourse of inhibition from slowest to fastest was GABAC receptors > glycine receptors > GABAA receptors. Deconvolution analysis showed that the distinct timing was due to differences in prolonged GABA and glycine release from amacrine cells. The timecourses of slow glycine release and GABA release onto GABAC receptors were reduced by Ca2+ buffering with EGTA-AM and BAPTA-AM, but faster GABA release on GABAA receptors was not, suggesting that release onto GABAA receptors is tightly coupled to Ca2+. The differential timing of GABA release was detected from spiking amacrine cells and not nonspiking A17 amacrine cells that form a reciprocal synapse with rod bipolar cells. Our results indicate that release from amacrine cells is inherently asynchronous and that the source of nonreciprocal rod bipolar cell inhibition differs between GABA receptors. The slow, differential timecourse of inhibition may be a mechanism to match the prolonged rod bipolar cell glutamate release and provide a way to temporally tune information across retinal pathways.
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Tian, Jide, Blake Middleton, and Daniel L. Kaufman. "GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice." Viruses 13, no. 6 (May 23, 2021): 966. http://dx.doi.org/10.3390/v13060966.
Full textAbstract:
There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.
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Ulloor, Jagadish, Vijayakumar Mavanji, Subhash Saha, Donald F. Siwek, and Subimal Datta. "Spontaneous REM Sleep Is Modulated By the Activation of the Pedunculopontine Tegmental GABAB Receptors in the Freely Moving Rat." Journal of Neurophysiology 91, no. 4 (April 2004): 1822–31. http://dx.doi.org/10.1152/jn.01104.2003.
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Considerable evidence suggests that the neurotransmitter γ-aminobutyric acid (GABA)-ergic system and pedunculopontine tegmentum (PPT) in the brain stem are critically involved in the regulation of rapid-eye-movement (REM) sleep. GABA and its various receptors are normally present in the PPT cholinergic cell compartment. The aim of this study was to identify the role of GABA and its receptors in the regulation of REM sleep. To achieve this aim, specific receptors were activated differentially by local microinjection of selective GABA receptor agonists into the PPT while quantifying its effects on REM sleep in freely moving chronically instrumented rats ( n = 21). The results demonstrated that when GABAB receptors were activated by local microinjection of a GABAB receptor selective agonist, baclofen, spontaneous REM sleep was suppressed in a dose-dependent manner. The optimum dose for REM sleep reduction was 1.5 nmol. In contrast, when GABAA and GABAC receptors were activated by microinjecting their receptor selective agonists, isoguvacine (ISGV) and cis-4-aminocrotonic acid (CACA), respectively, the total percentages of REM sleep did not change compared with the control values. In another eight freely moving rats, effects of baclofen application was tested on firing rates of REM-on cells ( n = 12). Of those 12 neurons, 11 stopped firing immediately after application of baclofen [latency: 50 ± 14 s (SD)] and remained almost silent for 130 ± 12 min. Findings of the present study provide direct evidence that the PPT GABAB receptors and REM-on cells are involved in the regulation of REM sleep.
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Kantrowitz, Joshua T., N. Noelle Francis, Alejandro Salah, and Katherine L. Perkins. "Synaptic Depolarizing GABA Response in Adults Is Excitatory and Proconvulsive When GABAB Receptors Are Blocked." Journal of Neurophysiology 93, no. 5 (May 2005): 2656–67. http://dx.doi.org/10.1152/jn.01026.2004.
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In the presence of 4-aminopyridine, interneurons fire synchronously, causing giant GABA-mediated postsynaptic potentials (GPSPs; GPSCs in voltage clamp) in CA3 pyramidal cells in hippocampal slices from adult guinea pigs. These triphasic GPSPs are composed of a GABAA-mediated hyperpolarizing component, a depolarizing component, and a GABAB-mediated hyperpolarizing component. We propose that GABAB receptors exert control over the postsynaptic depolarizing GABA response. Microelectrode and cell-attached recordings demonstrated that the mean number of action potentials during the depolarizing component of the GPSP increased dramatically in the presence of the GABAB receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2- hydroxypropyl](phenylmethyl) phosphinic acid (CGP 55845A; P = 0.003 and 0.0005, respectively). Whole cell voltage-clamp recordings showed that the postsynaptic GABAB and depolarizing GABA components of the GPSC overlap substantially, allowing the GABAB-mediated hyperpolarization to suppress the excitation mediated by the depolarizing GABA component. Further voltage-clamp recordings showed that CGP 55845A increased the duration of the depolarizing GABA component of the GPSC even when the GABAB component had already been blocked by internal QX-314, suggesting that CGP 55845A also increased the duration of GABA release. When glutamatergic transmission is intact, GPSPs directly precede epileptiform afterdischarges. We hypothesize that the depolarizing component of the GPSP triggers the epileptiform events and show here that enhancement of the depolarizing component with CGP 55845A increased epileptiform activity. CGP 55845A increased the likelihood of a GPSP triggering an epileptiform event from 32 to 99% ( P = 0.0000001), and significantly increased the number of afterdischarges per epileptiform event ( P = 0.001). Loss of GABAB receptor function is associated with temporal lobe epilepsy in rodents and humans. We show here that GABAB receptors exert control over the synaptic depolarizing GABA response and that block of GABAB receptors makes the depolarizing GABA response excitatory and proconvulsive.
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Galvan, Adriana, Rosa M. Villalba, Sara M. West, Nigel T. Maidment, Larry C. Ackerson, Yoland Smith, and Thomas Wichmann. "GABAergic Modulation of the Activity of Globus Pallidus Neurons in Primates: In Vivo Analysis of the Functions of GABA Receptors and GABA Transporters." Journal of Neurophysiology 94, no. 2 (August 2005): 990–1000. http://dx.doi.org/10.1152/jn.00068.2005.
Full textAbstract:
Neurons in the external and internal segment of the globus pallidus (GPe and GPi, respectively) receive substantial GABAergic inputs from the striatum and through axon collaterals of neighboring pallidal neurons. The effects of GABA on pallidal activity depend on the synaptic localization of GABA receptors and the distribution and activity of GABA transporters (GATs). To explore the contribution of GABA receptors and transporters to pallidal function, we recorded the activity of single neurons in GPe or GPi before, during, and after local microinjections of GABAergic compounds in awake rhesus monkeys. Activation of GABAA or GABAB receptors with muscimol or baclofen, respectively, inhibited pallidal activity. These effects were reversed by concomitant infusion of the respective GABA receptor antagonists, gabazine and CGP-55845. Given alone, the antagonists were without consistent effect. Application of the selective GAT-1 inhibitor, SKF-89976A, and the semiselective GAT-3 blocker, SNAP-5114, decreased pallidal activity. Both GAT inhibitors increased GABA levels in the pallidum, as measured by microdialysis. Electron microscopic observations revealed that these transporters are located on glial processes and unmyelinated axonal segments, but rarely on terminals. Our results indicate that activation of GABAA and GABAB receptors inhibits neuronal activity in both segments of the pallidum. GAT-1 and GAT-3 are involved in the modulation of endogenous GABA levels and may be important in regulating the extrasynaptic levels of GABA. Together with previous evidence that a considerable proportion of pallidal GABA receptors are located outside the synaptic cleft, our experiments strongly support the importance of extrasynaptic GABAergic transmission in the primate pallidum.
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Du, Jiu-Lin, and Xiong-Li Yang. "Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells." Journal of Neurophysiology 84, no. 2 (August 1, 2000): 666–76. http://dx.doi.org/10.1152/jn.2000.84.2.666.
Full textAbstract:
γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.