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At least 865 records · Page 48Linked to original sources
PubMed1992

Electrogenic uptake of gamma-aminobutyric acid by a cloned transporter expressed in Xenopus oocytes.

GAT-1, a gamma-aminobutyric acid (GABA) transporter cloned from rat brain, was expressed in Xenopus oocytes. Voltage-clamp measurements showed concentration-dependent, inward currents in response to GABA (K0.5 4.7 microM). The transport current required extracellular sodium and chloride ions; the Hill coefficient for chloride was 0.7, and that for sodium was 1.7. Correlation of current and [3H]GABA uptake measurements indicate that flux of one positive charge occurs per molecule of GABA transported. Membrane hyperpolarization from -40 to -100 mV increased the transport current approximately 3-fold. The results indicate that the transport of one molecule of GABA involves the co-transport of two sodium ions and one chloride ion.

Animals↗
PubMed1987

Is the concentration of gamma-aminobutyric acid in the nerve terminal regulated via product inhibition of glutamic acid decarboxylase?

Fractions of synaptosomes were used to study the regulation of gamma-aminobutyric acid (GABA) synthesis. The isolated synaptosomes were superfused in media of various compositions. [3H]GABA and GABA released into the medium or remaining in the synaptosomes were analyzed by liquid scintillation and HPLC techniques. Different conditions, designed to increase the GABA efflux rate were used: the rate of superfusion was varied and the concentrations of K+ and Ca2+ were altered. Stimulation of GABA efflux was paralleled with an increased synthesis of GABA, since, in spite of the increased GABA efflux, a relatively constant intraterminal level was found. The findings suggest that the intraterminal concentration of GABA and thus also its synthesis is regulated via product inhibition. In addition, [3H]GABA, exogenous, and GABA, endogenous, responded to external stimulae (Ca2+, veretradine, various GABA concentrations and the glutaminase inhibitor diazo-nor-leucine) in a way which was compatible with them being localized in and/or released from different compartments.

Animals↗
PubMed2001

Lactation alters gamma-aminobutyric acid neuronal activity in the hypothalamus and cerebral cortex in the rat.

Gamma-aminobutyric acid (GABA) neurons terminating in the hypothalamus have been implicated in the neuroendocrine regulation of reproductive hormones, particularly luteinizing hormone (LH) and prolactin. The aim of this study was to examine whether GABAergic neuronal activity in the hypothalamus was modified during lactation, and whether any observed changes correlated with changes in secretion of these hormones. Animals were divided into three experimental groups: diestrous controls, lactating with pups present (with pups), and lactating with pups removed for 4 h (without pups). Animals were decapitated either without treatment, or 60 min after inhibition of GABA degradation by aminooxyacetic acid (AOAA) (100 mg/kg, i.p.). The rate of GABA accumulation in the tissue after AOAA is a measure of GABA turnover. GABA turnover was estimated in 13 microdissected brain regions, and serum prolactin and LH measured by radioimmunoassay. Suckling was associated with significantly increased prolactin and significantly decreased LH compared with diestrous rats. In lactating rats with pups, GABA turnover was significantly increased in the cingulate cortex compared with diestrous rats. GABA turnover was significantly increased in the ventrolateral preoptic nucleus of lactating rats with pups compared with diestrous rats or lactating rats without pups. There was significantly lower GABA turnover in the anterior hypothalamic area, ventromedial and dorsomedial hypothalamic nuclei in lactating rats without pups compared with diestrous rats. There were no significant changes in other brain regions examined. The results demonstrate that activity of GABAergic neurons in specific parts of the hypothalamus and cerebral cortex is altered during lactation.

Animals↗
PubMed2006

Quantum dot-mediated detection of gamma-aminobutyric acid binding sites on the surface of living pollen protoplasts in tobacco.

gamma-Aminobutyric acid (GABA) is an inhibitory transmitter in the central nervous system of mammals. Recent investigations showed that it also plays an important role in regulating pollen tube growth and orientation in plants. To determine whether GABA receptors are also present on the membrane of pollen protoplasts, a fluorescence probe of quantum dots (QDs) was constructed and applied. The water-soluble CdSe-ZnS (core-shell) QDs were first synthesized and verified to possess good optical properties. GABA was then bioconjugated to the QDs in the presence of 1-ethyl-3-(3)-dimethylaminopropyl carbodiimide (EDC) and N-hydroxysuccinimide (NHS) to make the fluorescence probe. Using the probe, GABA binding sites were detected on the protoplast membrane of both pollen and somatic cells. Both the fluorescent signals on the surface of the protoplasts and the Ca(2+) oscillation assayed via the Ca(2+) probe Fluo-3/AM inside the protoplasts provided evidence that the potential GABA(B) receptors are present on the plant protoplast membrane.

Aniline Compounds↗
PubMed1997

Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition.

The gamma-aminobutyric acid (GABA) transporter GAT-1 is located in nerve terminals and catalyzes the electrogenic reuptake of the neurotransmitter with two sodium ions and one chloride. We now identify a single tyrosine residue that is critical for GABA recognition and transport. It is completely conserved throughout the superfamily, and even substitution to the other aromatic amino acids, phenylalanine (Y140F) and tryptophan (Y140W), results in completely inactive transporters. Electrophysiological characterization reveals that both mutant transporters exhibit the sodium-dependent transient currents associated with sodium binding as well as the chloride-dependent lithium leak currents characteristic of GAT-1. On the other hand, in both mutants GABA is neither able to induce a steady-state transport current nor to block their transient currents. The nontransportable analog SKF 100330A potently inhibits the sodium-dependent transient in the wild type GAT-1 but not in the Y140W transporter. It partly blocks the transient of Y140F. Thus, although sodium and chloride binding are unimpaired in the tyrosine mutants, they have a specific defect in the binding of GABA. The total conservation of the residue throughout the family suggests that tyrosine 140 may be involved in the liganding of the amino group, the moiety common to all of the neurotransmitters.

Biological Transport↗
PubMed1991

Action of gamma-aminobutyric acid (GABA) in the isolated photosensory pineal organ.

The effect of GABA (gamma-aminobutyric acid), its agonists (muscimol, baclofen) and antagonist (bicuculline) on pineal ganglion cells of the luminosity type were studied in the isolated, superfused pineal organ of the rainbow trout, Oncorhynchus mykiss. Extracellular recordings revealed that GABA added through the superfusion medium caused a clear alteration of the activity of projecting neurons, which transmit luminosity responses to the brain. Spontaneous discharges of ganglion cells were predominantly suppressed by GABA (33 neurons out of 48), but 10 neurons were clearly excited. Similar effects were observed after addition of muscimol, but not of baclofen. Bicuculline reversed the GABA and muscimol induced inhibition or excitation. In 4 neurons of the luminosity type, GABA caused bidirectional, inhibitory and excitatory responses depending on the state of light- or dark-adaptation. These observations suggest a role of a GABAergic mechanism in the generation and transmission of luminosity responses in the trout pineal organ. It appears that GABA participates in the modulation of light sensitivity during light- and dark-adaptation processes and that this action is mediated by GABAA receptors.

Animals↗
PubMed1994

Plasma concentrations of gamma-aminobutyric acid (GABA) and mood disorders: a blood test for manic depressive disease?

gamma-Aminobutyric acid (GABA), an inhibitory neurotransmitter that serves about one-third of brain neurons, is involved in the development of depression and in the treatment of depression and mania with pharmacological therapy. Brain activity of GABA may be conveniently measured in plasma, and changes in plasma concentrations of GABA reflect brain GABA activity. Plasma concentrations of GABA are significantly lower than control values in about one-third of patients with major depressive disorder; concentrations are also low in patients with mania and in bipolar patients who are depressed. These low concentrations of GABA appear to persist after recovery from depression and are not increased by treatments that improve depressive symptoms. Follow-up studies suggest that GABA concentrations remain relatively constant over at least 4 years. Additionally, preliminary data suggest that low plasma GABA is a familial marker of mood disorders in a subset of patients. Despite the difficulty of demonstrating that a particular biochemical measure is a true genetic trait marker for vulnerability for development of an illness, the accumulated data suggest that low plasma GABA may represent a biological marker of vulnerability for development of various mood disorders.

Affective Disorders, Psychotic↗
PubMed1988

Patch-clamp study of gamma-aminobutyric acid receptor Cl- channels in cultured astrocytes.

The membrane channels operated by gamma-aminobutyric acid (GABA) were studied in cultured astrocytes from rat cerebral hemispheres by using patch-clamp techniques. The channel properties appeared to be very similar, in many respects, to those present in neuronal cell membranes. The Cl- -selective channels were activated after the sequential binding of two GABA molecules to the receptor, as deduced from the slope of the dose-response curve. Single-channel currents displayed multiple conductance states of 12 pS, 21 pS, 29 pS, and 43 pS, with the main-state conductance being 29 pS. The gating properties could be described by a sequential reaction scheme for agonist-activated channels. GABA-induced whole-cell currents were potentiated by the benzodiazepine receptor agonist diazepam and also, to a lesser extent, by methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate an inverse agonist. In neurons and chromaffin cells, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate reduces the sensitivity of the GABA receptor, indicating that neuronal and glial GABA/benzodiazepine receptor--Cl- channel complexes are different. Glial GABA receptor channels could be of functional importance in buffering extracellular Cl- in the cleft of the GABAergic synapse.

Animals↗
PubMed1981

Reductions in retinal gamma-aminobutyric acid (GABA) content and in [3H]flunitrazepam binding after postnatal monosodium glutamate injections in rats.

Specific binding of [3H]flunitrazepam is found in the mammalian retina and its characteristics are similar in important respects to those in the cerebral cortex. Numerous reports have shown that monosodium glutamate (MSG) given neonatally to rats results in neuronal cell death with sparing of photoreceptor and glial cells. Sprague-Dawley rats were given MSG (3.2 mg/g i.p.) from day 2 to day 12 after birth; controls received equimolar injections of NaCl. At 8 to 9 weeks of age, the rats were killed and [3H]flunitrazepam binding was examined in the retinas are various brain regions. Histologic evidence showed the virtual absence of ganglion cells and a marked reduction of neurons in the inner nuclear layer of retinas from MSG-treated rats; photoreceptor and Muller cells appeared normal. In the retinas from MSG-treated rats, gamma-aminobutyric acid levels were decreased by 73% and the Bmax of [3H]flunitrazepam binding was decreased by 77%; there was no change in Kd. In the cerebellum, cerebral cortex and hypothalamus of MSG-treated rats, [3H]flunitrazepam binding was unchanged. These results strengthen the association of gamma-aminobutyric acid mechanisms with benzodiazepine binding and suggest a predominant neuronal localization of the binding sites.

Animals↗
PubMed1979

Intra-axonal diffusion of [3H]acetylcholine and [3H]gamma-aminobutyric acid in a neurone of Aplysia.

1. [3H]acetylcholine (ACh) or [3H]gamma-aminobutyric acid (GABA) was injected into the cell body of a cholinergic neurone of Aplysia kurodai. 2. [3H]ACh moved down the axon at a maximum speed of 2.5 mm/sec at 20 degrees C. 3. 20 mM-colchicine suppressed this movement, but some passive movement of radioactivity was noted along the axon. 4. Profiles of the passive movement coincided with theoretically obtained diffusion profiles. 5. The diffusion coefficient of ACh in the axoplasm was estimated. It was 3 x 10(-6) cm2/sec at 5 degrees C, 4 X 10(-6) cm2/sec at 15 degrees C and 6.5 x 10(-6) cm2/sec at 30 degrees C. The Q10 was 1.35, the activation energy was about 5 kcal/degrees C. These diffusion coefficients were lower than that of free diffusion of ACh (8 x 10(-6) cm2/sec at 18 degrees C, Fatt, 1954), and assumed to be reasonable, if one considers frictional resistivity of axoplasm in the diffusion of ACh molecules. 6. [3H]GABA diffused similarly to ACh, and the diffusion coefficients agreed with the estimated value when the molecular size differences were taken into account. 7. Both ACh and GABA seemed to diffuse in soluble form or as single molecules in the axoplasm. 8. Intra-axonal diffusion is very effective for short distances.

Acetylcholine↗
PubMed1997

Effects of 3,3-dipyridylmethyl-1-phenyl-2-indolinone on gamma-aminobutyric acid elicited chloride current of snail central neuron.

The effects of (1) gamma-aminobutyric acid (GABA) on the excitable membrane and (2) DPMPI (3,3-dipyridylmethyl-1-phenyl-2-indolinone) on the microperfused GABA elicited currents were investigated on central LP5 neuron of giant African snail, Achatina fulica Ferussac, with conventional voltage-clamp technique. GABA elicited an inward current of LP5 neuron by a concentration and voltage dependent manner. Muscimol, GABAA receptor agonist, did, while baclofen, GABAB receptor agonist, did not, elicit the membrane current on the neuron. The GABA elicited currents in LP5 neuron were blocked by picrotoxin, a GABAA receptor ion channel complex antagonist while the currents were not blocked by phaclofen, a GABAB receptor antagonist. The results suggested that the GABA elicited current in LP5 neuron was mainly due to activation of GABAA receptor. DPMPI increased the frequency of the spontaneously generated action potential of the neuron. In the voltage clamped neuron, DPMPI decreased the GABA elicited responses by a concentration dependent manner. DPMPI altered neither the reversal potential of GABA elicited current, nor the membrane resistance of the excitable membrane of central LP5 neuron. The results concluded that DPMPI altered the GABAA activated receptor ionic channel complex of the LP5 neuron.

Action Potentials↗
PubMed2005

The multiple facets of gamma-aminobutyric acid dysfunction in epilepsy.

PURPOSE OF REVIEW: The polarity of action of gamma-aminobutyric acid (GABA) changes from inhibition to excitation in the developing brain and in epilepsies. This review deals with recent observations concerning the mechanisms and clinical implications of the shift in GABA's activity from inhibition to excitation. RECENT FINDINGS: GABAergic synapses provide most transmitter-gated inhibition and are the targets of numerous clinically active agents, notably antiepileptic drugs. In a wide range of brain structures and species, GABAergic synapses are excitatory during maturation because of a higher concentration of intracellular chloride. These findings suggest that activation of GABA synapses will excite foetal neurones while inhibiting those of the mother. In epilepsies, recurrent seizures also lead to an accumulation of chloride and an excitatory action of GABA. These observations have major implications for clinical practice and research. They suggest that use of benzodiazepines by pregnant mothers may lead to deleterious consequences when they are taken during the period when GABA is the main excitatory transmitter. Because neuronal activity alters important cell functions, including migration and morphogenesis, aberrant excessive excitation may lead to profound deleterious consequences. SUMMARY: In several physiological and pathological conditions, activation of GABAergic synapses excites neurones instead of producing classical inhibition. This shift, which is due to an intracellular accumulation of chloride, has major consequences for both the operation of networks and the pathogenic effects of epilepsies. This is particularly important in the immature brain, where the excitatory actions of GABA are particularly prominent.

Brain Chemistry↗
PubMed2000

Ca(2+) requirement for high-affinity gamma-aminobutyric acid (GABA) binding at GABA(B) receptors: involvement of serine 269 of the GABA(B)R1 subunit.

The gamma-aminobutyric acid (GABA) receptor type B (GABA(B)R) is constituted of at least two homologous proteins, GABA(B)R1 and GABA(B)R2. These proteins share sequence and structural similarity with metabotropic glutamate and Ca(2+)-sensing receptors, both of which are sensitive to Ca(2+). Using rat brain membranes, we report here that the affinity of GABA and 3-aminopropylphosphinic acid for the GABA(B)R receptor is decreased by a factor >10 in the absence of Ca(2+). Such a large effect of Ca(2+) is not observed with baclofen or the antagonists CGP64213 and CGP56999A. In contrast to baclofen, the potency of GABA in stimulating GTPgammaS binding in rat brain membranes is also decreased by a factor >10 upon Ca(2+) removal. The potency for Ca(2+) in regulating GABA affinity was 37 microM. In cells expressing GABA(B)R1, the potency of GABA, but not of baclofen, in displacing bound (125)I-CGP64213 was similarly decreased in the absence of Ca(2+). To identify residues that are responsible for the Ca(2+) effect, the pharmacological profile and the Ca(2+) sensitivity of a series of GABA(B)R1 mutants were examined. The mutation of Ser269 into Ala was found to decrease the affinity of GABA, but not of baclofen, and the GABA affinity was found not to be affected upon Ca(2+) removal. Finally, the effect of Ca(2+) on the GABA(B) receptor function is no longer observed in cells coexpressing this GABA(B)R1-S269A mutant and the wild-type GABA(B)R2. Taken together, these results show that Ser269, which is conserved in the GABA(B)R1 protein from Caenorhabditis elegans to mammals, is critical for the Ca(2+)-effect on the heteromeric GABA(B) receptor.

Amino Acid Sequence↗
PubMed2003

Residues in the extracellular loop 4 are critical for maintaining the conformational equilibrium of the gamma-aminobutyric acid transporter-1.

We mutated residues Met345 and Thr349 in the rat gamma-aminobutyric acid transporter-1 (GAT-1) to histidines (M345H and T349H). These two residues are located four amino acids apart at the extracellular end of transmembrane segment 7 in a region of GAT-1 that we have previously suggested undergoes conformational changes critical for the transport process. The two single mutants and the double mutant (M345H/T349H) were expressed in Xenopus laevis oocytes, and their steady-state and presteady-state kinetics were examined and compared with wild type GAT-1 by using the two-electrode voltage clamp method. Oocytes expressing M345H showed a decrease in apparent GABA affinity, an increase in apparent affinity for Na+, a shift in the charge/voltage (Q/Vm) relationship to more positive membrane potentials, and an increased Li+-induced leak current. Oocytes expressing T349H showed an increase in apparent GABA affinity, a decrease in apparent Na+ affinity, a profound shift in the Q/Vm relationship to more negative potentials, and a decreased Li+-induced leak current. The data are consistent with a shift in the conformational equilibrium of the mutant transporters, with M345H stabilized in an outward-facing conformation and T349H in an inward-facing conformation. These data suggest that the extracellular end of transmembrane domain 7 not only undergoes conformational changes critical for the translocation process but also plays a role in regulating the conformational equilibrium between inward- and outward-facing conformations.

Animals↗
PubMed2006

Identification of a lithium interaction site in the gamma-aminobutyric acid (GABA) transporter GAT-1.

The sodium- and chloride-dependent electrogenic gamma-aminobutyric acid (GABA) transporter GAT-1, which transports two sodium ions together with GABA, is essential for synaptic transmission by this neurotransmitter. Although lithium by itself does not support GABA transport, it has been proposed that lithium can replace sodium at one of the binding sites but not at the other. To identify putative lithium selectivity determinants, we have mutated the five GAT-1 residues corresponding to those whose side chains participate in the sodium binding sites Na1 and Na2 of the bacterial leucine-transporting homologue LeuT(Aa). In GAT-1 and in most other neurotransmitter transporter family members, four of these residues are conserved, but aspartate 395 replaces the Na2 residue threonine 354. At varying extracellular sodium, lithium stimulated sodium-dependent transport currents as well as [3H]GABA uptake in wild type GAT-1. The extent of this stimulation was dependent on the GABA concentration. In mutants in which aspartate 395 was replaced by threonine or serine, the stimulation of transport by lithium was abolished. Moreover, these mutants were unable to mediate the lithium leak currents. This phenotype was not observed in mutants at the four other positions, although their transport properties were severely impacted. Thus at saturating GABA, the site corresponding to Na2 behaves as a low affinity sodium binding site where lithium can replace sodium. We propose that GABA participates in the other sodium binding site, just like leucine does in the Na1 site, and that at limiting GABA, this site determines the apparent sodium affinity of GABA transport.

Binding Sites↗
PubMed2000

An initiator element mediates autologous downregulation of the human type A gamma -aminobutyric acid receptor beta 1 subunit gene.

The regulated expression of type A gamma-aminobutyric acid receptor (GABA(A)R) subunit genes is postulated to play a role in neuronal maturation, synaptogenesis, and predisposition to neurological disease. Increases in GABA levels and changes in GABA(A)R subunit gene expression, including decreased beta1 mRNA levels, have been observed in animal models of epilepsy. Persistent exposure to GABA down-regulates GABA(A)R number in primary cultures of neocortical neurons, but the regulatory mechanisms remain unknown. Here, we report the identification of a TATA-less minimal promoter of 296 bp for the human GABA(A)R beta1 subunit gene that is neuron specific and autologously down-regulated by GABA. beta1 promoter activity, mRNA levels, and subunit protein are decreased by persistent GABA(A)R activation. The core promoter, 270 bp, contains an initiator element (Inr) at the major transcriptional start site. Three concatenated copies of the 10-bp Inr and its immediate 3' flanking sequence produce full neural specific activity that is down-regulated by GABA in transiently transfected neocortical neurons. Taking these results together with those of DNase I footprinting, electrophoretic mobility shift analysis, and 2-bp mutagenesis, we conclude that GABA-induced down-regulation of beta1 subunit mRNAs involves the differential binding of a sequence-specific basal transcription factor(s) to the Inr. The results support a transcriptional mechanism for the down-regulation of beta1 subunit GABA(A)R gene expression and raises the possibility that altered levels of sequence-specific basal transcription factors may contribute to neurological disorders such as epilepsy.

Animals↗
PubMed2001

Rostral ventrolateral medulla suppresses reflex bradycardia by the release of gamma-aminobutyric acid in nucleus tractus solitarii of the rat.

We investigated the role of gamma-aminobutyric acid (GABA) in the nucleus tractus solitarii (NTS), the principal recipient of baroreceptor afferent fibers in the medulla oblongata, in the suppression of cardiac baroreceptor reflex (BRR) response by the rostral ventrolateral medulla (RVLM). Direct microinfusion via reverse microdialysis of L-glutamate (50 microM) into the RVLM promoted an inhibition of the BRR response, alongside an increase in the concentration of GABA in the dialysate collected from the ipsilateral NTS. Such an increase in GABA concentration in the NTS to RVLM activation was site-specific, as microinfusion of L-glutamate into areas outside the confines of RVLM resulted in no discernible change in GABA concentration in the dialysate of the NTS and minimal effect on the cardiac BRR response. The RVLM-induced BRR suppression of cardiac BRR response to microinjection into the bilateral RVLM of L-glutamate (1 nmol) was antagonized by administration into the bilateral NTS of the GABA(A) receptor antagonist, bicuculline methiodide (1 or 5 pmol), or the GABA(B) receptor antagonist, 2-hydroxy-saclofen (100 or 500 pmol). These results suggest that GABA released in the NTS may participate in cardiac BRR suppression induced by glutamatergic activation of the RVLM, via an action on both GABA(A) and GABA(B) receptor subtypes.

Afferent Pathways↗
PubMed1992

Response of oligodendrocytes to glutamate and gamma-aminobutyric acid in the intact mouse optic nerve.

The electrophysiological response to glutamate and gamma-aminobutyric acid (GABA) is determined in oligodendrocytes of the isolated intact mouse optic nerve, identified by their characteristic morphology following iontophoretic injection with horseradish peroxidase (HRP). In this study, mature myelin-forming oligodendrocytes are shown for the first time to respond to glutamate and GABA in situ, by a 2-3 mV depolarization. Morphologically homogeneous oligodendrocytes exhibit a heterogeneous response to glutamate and GABA; some cells respond to both excitatory amino acids, whereas others respond to one but not the other, and some oligodendrocytes do not respond to either. Oligodendrocytes uniformly depolarize in elevated [K+]o and it is concluded that the effect of glutamate and GABA is not mediated by an increase in [K+]o released from axons or astrocytes. The oligodendrocyte response to amino acids may be important in axon-to-oligodendrocyte signalling at the nodes of Ranvier.

Animals↗