Gamma-aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues
01 Oct 1995-Comparative Biochemistry and Physiology Part A: Physiology (Pergamon)-Vol. 112, Iss: 2, pp 247-263
TL;DR: GABA, a major inhibitory neurotransmitter of mammalian central nervous system, is found in a wide range of organisms, from prokaryotes to vertebrates, and is also present in a variety of circulating cells, including platelets and lymphocytes.
About: This article is published in Comparative Biochemistry and Physiology Part A: Physiology.The article was published on 1995-10-01. It has received 180 citations till now. The article focuses on the topics: gamma-Aminobutyric acid & Glutamate decarboxylase.
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TL;DR: In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.
Abstract: γ-Aminobutyrate (GABA) is a major inhibitory neurotransmitter in the adult mammalian brain. GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues. GABA is synthesized primarily from glutamate by glutamate decarboxylase (GAD), but alternative pathways may be important under certain situations. Two types of GAD appear to have significant physiological roles. GABA functions appear to be triggered by binding of GABA to its ionotropic receptors, GABAAand GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB. The physiological, pharmacological, and molecular characteristics of GABAA receptors are well documented, and diversity in the pharmacologic properties of the receptor subtypes is important clinically. In addition to its role in neural development, GABA appears to be involved in a wide variety of physiological functions in tissues and organs outside the brain.
529 citations
TL;DR: It is proposed that changes in GABA activity may be instrumented to modulate plasticity purposefully; for instance, to enhance plastic change and recovery of function after a lesion in neurological patients.
Abstract: Motor practice may lead to expansion of trained representations in the motor cortex, but it is unknown whether this practice-dependent plasticity can be purposefully enhanced or depressed. Evidence, mainly based on animal experiments, indicates that the activity of GABA-related cortical inhibition is important in controlling the extent to which plasticity may occur. We tested the role of GABA in modulating practice-dependent plasticity in the human motor cortex. A decrease in GABA-related cortical inhibition was achieved by ischaemic nerve block (INB) in the hand by deafferentation/deefferentation and an increase was achieved by administration of the GABA(A) receptor agonist lorazepam. In Experiment 1, healthy subjects performed motor practice (MP), consisting of repeated ballistic contractions of the biceps muscle in the absence (MP alone) or presence of INB (MP+INB). Changes in the biceps motor cortex representation were assessed by transcranial magnetic stimulation (TMS). MP+INB resulted in a dramatic increase in the size of the motor evoked potential (MEP) and in paired-pulse excitability compared with mild or no changes in the MP-alone and INB-alone conditions. In Experiment 2, this dramatic increase in biceps representation induced by MP+INB was replicated when subjects were pretreated with placebo, but this increase was prevented or even switched to a decrease when subjects were pretreated with lorazepam. These findings indicate that a decrease in GABA-related inhibition facilitates practice-dependent plasticity in the human motor cortex, whereas an increase depresses it. In Experiment 3, practice-dependent plasticity (assessed by TMS, as in the first two experiments) was also tested at the behavioural level. The dramatic increase in biceps MEP size induced by MP+INB was paralleled by an increase in peak acceleration of the fastest elbow flexion movements. Similarly, the lack of change in MEP size in the MP-alone condition was paralleled by a lack of change in peak acceleration. We propose that changes in GABA activity may be instrumented to modulate plasticity purposefully; for instance, to enhance plastic change and recovery of function after a lesion in neurological patients.
479 citations
Cites background from "Gamma-aminobutyric acid (GABA) meta..."
...GABA is produced in the nerve terminals of GABAergic neurones from glutamate and glutamic acid byknowledge that other forms of motor cortex plasticity require defined sensory input for their occurrence (Hamdy et al., glutamic acid decarboxylase and is catabolized by GABA transaminase (GABA-T) (Tillakaratne et al., 1995)....
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...In our experiments, one would then propose abecause it could be blocked if the subjects were pretreated with an NMDA receptor antagonist (Ziemann et al., 1998c). deafferentation-induced increase in GABA-T activity to explain the rapid decrease in GABA level....
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...…nerve terminals of GABAergic neurones from glutamate and glutamic acid byknowledge that other forms of motor cortex plasticity require defined sensory input for their occurrence (Hamdy et al., glutamic acid decarboxylase and is catabolized by GABA transaminase (GABA-T) (Tillakaratne et al., 1995)....
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...Keywords: practice-dependent plasticity; GABA-related inhibition; modulation of plasticity; human motor cortex; transcranial magnetic stimulation Abbreviations: APB abductor pollicis brevis muscle; ES electrical stimulation; GABA-T GABA transaminase; INB ischaemic nerve block; LTD long-term depression; LTP long-term potentiation; MEP motor evoked potential; MP motor practice; MT motor threshold; NMDA N-methyl-D-aspartate; PAS passive movement of the elbow; PPE paired-pulse excitability; STP short-term potentiation; rTMS repetitive TMS; TMS transcranial magnetic stimulation...
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...This suggests that rapid modulation of GABA-T activity provides a candidate mechanism toinduced by rTMS of the motor cortex during INB-induced disinhibition depended on the activation of NMDA receptors explain the change in GABA concentration that occurs within 1 min....
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TL;DR: A role for the GABA shunt is established in preventing the accumulation of reactive oxygen intermediates and cell death, which appears to be essential for plant defense against environmental stress.
Abstract: The gamma-aminobutyrate (GABA) shunt is a metabolic pathway that bypasses two steps of the tricarboxylic acid cycle, and it is present in both prokaryotes and eukaryotes. In plants the pathway is composed of the calcium/calmodulin-regulated cytosolic enzyme glutamate decarboxylase and the mitochondrial enzymes GABA transaminase and succinic-semialdehyde dehydrogenase (SSADH). The activity of the GABA shunt in plants is rapidly enhanced in response to various biotic and abiotic stresses. However the physiological role of this pathway remains obscure. To elucidate its role in plants, we analyzed Arabidopsis T-DNA knockout mutants of SSADH, the ultimate enzyme of the pathway. Four alleles of the ssadh mutation were isolated, and these exhibited a similar phenotype. When exposed to white light (100 micromol of photons per m2 per s), they appear dwarfed with necrotic lesions. Detailed spectrum analysis revealed that UV-B has the most adverse effect on the mutant phenotype, whereas photosynthetic active range light has a very little effect. The ssadh mutants are also sensitive to heat, as they develop necrosis when submitted to such stress. Moreover, both UV and heat cause a rapid increase in the levels of hydrogen peroxide in the ssadh mutants, which is associated with enhanced cell death. Surprisingly, our study also shows that trichomes are hypersensitive to stresses in ssadh mutants. Our work establishes a role for the GABA shunt in preventing the accumulation of reactive oxygen intermediates and cell death, which appears to be essential for plant defense against environmental stress.
358 citations
TL;DR: It is concluded that CaM binding to GAD is essential for the regulation of GABA and glutamate metabolism, and that regulation of GAD activity is necessary for normal plant development.
Abstract: Glutamate decarboxylase (GAD) catalyzes the decarboxylation of glutamate to CO2 and gamma-aminobutyrate (GABA). GAD is ubiquitous in prokaryotes and eukaryotes, but only plant GAD has been shown to bind calmodulin (CaM). Here, we assess the role of the GAD CaM-binding domain in vivo. Transgenic tobacco plants expressing a mutant petunia GAD lacking the CaM-binding domain (GADdeltaC plants) exhibit severe morphological abnormalities, such as short stems, in which cortex parenchyma cells fail to elongate, associated with extremely high GABA and low glutamate levels. The morphology of transgenic plants expressing the full-length GAD (GAD plants) is indistinguishable from that of wild-type (WT) plants. In WT and GAD plant extracts, GAD activity is inhibited by EGTA and by the CaM antagonist trifluoperazine, and is associated with a CaM-containing protein complex of approximately 500 kDa. In contrast, GADdeltaC plants lack normal GAD complexes, and GAD activity in their extracts is not affected by EGTA and trifluoperazine. We conclude that CaM binding to GAD is essential for the regulation of GABA and glutamate metabolism, and that regulation of GAD activity is necessary for normal plant development. This study is the first to demonstrate an in vivo function for CaM binding to a target protein in plants.
272 citations
Cites background from "Gamma-aminobutyric acid (GABA) meta..."
...It is also involved in other processes, such as the control of hormone release in endocrine cells in the pancreas, adrenal medulla and the gastrointestinal tract in animals (Tillakaratne et al., 1995)....
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TL;DR: It is found that MoAP1 is highly expressed in conidia and during invasive hyphal growth, and regulates transcriptions of M. oryzae that are important in the growth, development, and pathogenicity of the fungus.
Abstract: Saccharomyces cerevisiae Yap1 protein is an AP1-like transcription factor involved in the regulation of the oxidative stress response. An ortholog of Yap1, MoAP1, was recently identified from the rice blast fungus Magnaporthe oryzae genome. We found that MoAP1 is highly expressed in conidia and during invasive hyphal growth. The Moap1 mutant was sensitive to H2O2, similar to S. cerevisiae yap1 mutants, and MoAP1 complemented Yap1 function in resistance to H2O2, albeit partially. The Moap1 mutant also exhibited various defects in aerial hyphal growth, mycelial branching, conidia formation, the production of extracellular peroxidases and laccases, and melanin pigmentation. Consequently, the Moap1 mutant was unable to infect the host plant. The MoAP1-eGFP fusion protein is localized inside the nucleus upon exposure to H2O2, suggesting that MoAP1 also functions as a redox sensor. Moreover, through RNA sequence analysis, many MoAP1-regulated genes were identified, including several novel ones that were also involved in pathogenicity. Disruption of respective MGG_01662 (MoAAT) and MGG_02531 (encoding hypothetical protein) genes did not result in any detectable changes in conidial germination and appressorium formation but reduced pathogenicity, whereas the mutant strains of MGG_01230 (MoSSADH) and MGG_15157 (MoACT) showed marketed reductions in aerial hyphal growth, mycelial branching, and loss of conidiation as well as pathogenicity, similar to the Moap1 mutant. Taken together, our studies identify MoAP1 as a positive transcription factor that regulates transcriptions of MGG_01662, MGG_02531, MGG_01230, and MGG_15157 that are important in the growth, development, and pathogenicity of M. oryzae.
257 citations
Cites background from "Gamma-aminobutyric acid (GABA) meta..."
...The c-aminobutyrate (GABA) shunt is a metabolic pathway that bypasses two successive steps of the tricarboxylic acid (TCA) cycle and is present in many organisms [85,86,87]....
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References
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TL;DR: The pancreatic islet β-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM), has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA.
Abstract: The pancreatic islet β-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (γ-aminobutyric acid). Pancreatic β cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.
1,522 citations
TL;DR: The brain contains two forms of the GABA synthetic enzyme glutamate decarboxylase (GAD), which differ in molecular size, amino acid sequence, antigenicity, cellular and subcellular location, and interaction with the GAD cofactor pyridoxal phosphate.
1,198 citations
TL;DR: Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines.
Abstract: The major type of receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), called the GABAA receptor, is a member of a gene superfamily of ligand-gated ion channels. This receptor is a hetero-oligomeric protein composed of several distinct polypeptide types (alpha, beta, gamma, and delta). Molecular cloning of these polypeptides reveals that they show 20-40% identity with each other, and 10-20% identity with polypeptides of the nicotinic acetylcholine receptors and strychnine-sensitive glycine receptor. Each polypeptide type is also represented by a family of genes whose members have 60-80% amino acid sequence identity. Regions of conserved and variable amino acid sequence suggest structural and functional domains within each polypeptide. All of the polypeptides when expressed in heterologous cells produce GABA-activated chloride channels, and the different subtypes express different pharmacological properties. The distributions of mRNAs for the different GABAA receptor polypeptides and their subtypes show significant brain regional variation consistent with pharmacological and biochemical evidence for receptor heterogeneity. Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines. The properties of the different subpopulations of GABAA receptors are determined by which one or more of the different polypeptides and their subtypes are expressed in a given cell to produce a variety of different oligomeric protein structures. Molecular cloning techniques have produced rapid advances in understanding the GABAA receptor protein family.
971 citations
TL;DR: It is suggested that the relative levels of apo‐GAD65 and holo‐ GAD65 in synaptic terminals may couple GABA production to neuronal activity.
Abstract: Glutamate decarboxylase (GAD) catalyzes the production of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter. The mammalian brain contains two forms of GAD, with Mrs of 67,000 and 65,000 (GAD67 and GAD65). Using a new antiserum specific for GAD67 and a monoclonal antibody specific for GAD65, we show that the two forms of GAD differ in their intraneuronal distributions: GAD67 is widely distributed throughout the neuron, whereas GAD65 lies primarily in axon terminals. In brain extracts, almost all GAD67 is in an active holoenzyme form, saturated with its cofactor, pyridoxal phosphate. In contrast, only about half of GAD65 (which is found in synaptic terminals) exists as active holoenzyme. We suggest that the relative levels of apo-GAD65 and holo-GAD65 in synaptic terminals may couple GABA production to neuronal activity.
796 citations
TL;DR: The findings suggest that the two isoforms of GAD are present in most classes of GABA neurons but that they are not similarly distributed within the neurons.
Abstract: Two isoforms of glutamic acid decarboxylase (GAD67 and GAD65) and their mRNAs were localized in the rat brain by immunohistochemistry and nonradioactive in situ hybridization methods with digoxigenin-labeled cRNA probes. In most brain regions, both GAD isoforms were present in neuronal cell bodies as well as axon terminals. A few populations of neurons, such as those in the reticular nucleus of the thalamus, exhibited similar cell body labeling for both GADs. However, in many brain regions, the cell bodies that were immunoreactive for GAD67 were often more numerous than those that were immunoreactive for GAD65. In contrast, the density (quantity) of GAD65-immunoreactive axon terminals was higher than that of GAD67-immunoreactive terminals. Strong parallels were observed between the intensity of immunohistochemical labeling of cell bodies and the levels of mRNA labeling for both GAD isoforms. Many groups of GAD-containing cell bodies were distinctly labeled for GAD67, and these same groups of neurons were heavily labeled for GAD67 mRNA. Such neurons included Purkinje cells of the cerebellar cortex, nonpyramidal cells in the cerebral cortex, and neurons of the reticular nucleus of the thalamus. Similar parallels in labeling were observed for GAD65 and its mRNA. Distinct cell body labeling for the protein and associated high levels of GAD65 mRNA were found in neurons of the reticular nucleus of the thalamus and periglomerular cells in the olfactory bulb. However, many cell bodies were not readily labeled for GAD65 with immunohistochemical methods. Such absence or weakness of cell body labeling for the protein was associated with low or moderate levels of GAD65 mRNA. Even though light cell body staining was frequently observed for GAD65 and its mRNA, strong axon terminal labeling for GAD65 was present. Thus, in the deep cerebellar nuclei to which the Purkinje cells of the cerebellar cortex project, strong terminal labeling was observed for both GAD isoforms even though only light cell body labeling of the Purkinje cells was obtained for GAD65 and its mRNA. The findings suggest that the two isoforms of GAD are present in most classes of GABA neurons but that they are not similarly distributed within the neurons. GAD67 is present in readily detectable amounts in many GAD-containing cell bodies whereas GAD65 is particularly prominent in many axon terminals. In addition, neurons that express either form of GAD mRNA also express the corresponding protein. Levels of labeling for the GAD mRNAs suggest that, under normal conditions, the synthesis of GAD65 is frequently lower than that of GAD67.(ABSTRACT TRUNCATED AT 400 WORDS)
604 citations