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PubMedDate not supplied

[Effect of emotional-pain stress on the activity of the gamma-aminobutyric acid system].

In experiments on rats the emotional-pain stress is studied for its effect on the activity of the gamma-aminobutyric acid (GABA) system in the forebrain and stem structures, on GABA catabolism and GABA metabolism-related energy metabolism indices in the hippocamp and frontal cortex neurons. It is shown that the stress effect is accompanied by the GABA level increase and GABA-transaminase inhibition with a simultaneous rise of the succinate dehydrogenase and glutamate dehydrogenase activity. The pain factor is established to be very important for changes in the activity of GABA-transaminase and succinate dehydrogenase. The found shifts in the GABA activity system are significant for neuromediatory and energy adaptation to the stress.

4-Aminobutyrate Transaminase↗

PubMed2005

Selective determination of gamma-aminobutyric acid, glutamate and alanine by mixed micellar electrokinetic chromatography and fluorescence detection.

A mixed micellar electrokinetic chromatography method with fluorescence detection was developed to simultaneously monitor gamma-aminobutyric acid (GABA), glutamate (Glu) and alanine (Ala) in biological samples. Amino acids were derivatized with naphthalene-2,3-dicarboxaldehyde (NDA). The separation of three NDA-labeled isomers (GABA, alpha-ABA, beta-ABA) was studied in detail with different micelles solutions such as sodium dodecyl sulfate (SDS), beta-cyclodextrin (beta-CD) and sodium cholate (SC). Simultaneous resolution of GABA, Glu and Ala from 21 amino acids was achieved within 5 min using 20 mM phosphate buffer at pH 8.7 containing 24 mM SC and 26 mM SDS. The detection limits were 4.0 x 10(-8), 1.1 x 10(-8) and 1.3 x 10(-8) M, for GABA, Glu and Ala, respectively, with S/N = 2. The method was applied to monitor the changes of amount of GABA, Glu and Ala in tobacco leaf in response to cold and dark stress.

Alanine↗

PubMed1986

Light- and electron-microscopic visualization of gamma-aminobutyric acid and GABA-transaminase in the oviduct of rats. Predominant occurrence in epithelium.

The distribution in the rat oviduct of gamma-aminobutyric acid and its catabolic enzyme GABA-transaminase was studied by the use of immunocytochemical and enzyme-histochemical techniques. At the light-microscopic level, both GABA immunoreactivity and GABA-transaminase enzyme reactivity were found primarily in the tubal epithelium while in the muscle layers of the organ only a faint GABA and GABA-transaminase positive staining could be detected. Electron-microscopic evaluation of the GABA immunoreactivity revealed a heavy labelling of the basal bodies (kinetosomes) and a moderate staining of the cilia. These findings indicate that the role of GABA in the oviduct is not related to neurotransmission but may be related to ciliary functions.

4-Aminobutyrate Transaminase↗

PubMed1999

Subcellular localization and endocytosis of homomeric gamma2 subunit splice variants of gamma-aminobutyric acid type A receptors.

The expression of alpha and beta gamma-aminobutyric acid type A receptor subunits produces GABA-gated channels which require the incorporation of either the gamma2 or gamma3 subunit for benzodiazepine modulation. Here we examine the role of the gamma2 subunit splice variants, gamma2S and gamma2L which differ by eight amino acids in the major intracellular domain, in mediating cell surface expression. Using immunocytochemistry we have demonstrated that when expressed alone, the gamma2S subunit can access the cell surface and internalize constitutively. In contrast, alpha1, beta2 and gamma2L are retained predominantly in the endoplasmic reticulum (ER) when expressed alone. Replacing the insert which differentiates gamma2L from gamma2S (LLRMFSFK) with eight alanines produces a phenotype identical to gamma2S. Both gamma2 subunits fail to produce high molecular weight oligomers observed for alpha1beta2 and alpha1beta2gamma2 heterooligomers and do not form functional ion channels. Surface expression of gamma2S is repressed upon the coexpression of alpha1 or beta2 subunits, resulting in ER-retained heterooligomers, suggesting that homomeric gamma2S is unlikely to occur in vivo. However, its independent maturation to surface competence and preferential assembly with alpha and beta subunits may ensure the production of functional benzodiazepine-sensitive receptors. Furthermore, the presence of the gamma2 subunit appears to confer an endocytotic capacity to these heterooligomeric receptors.

Animals↗

PubMed1984

The gamma-aminobutyric acid receptor in catfish brain.

When the binding of [3H]gamma-aminobutyric acid (GABA) to its receptor in catfish synaptic membranes was studied, a high affinity (Kd = 8.4 nM) and a low affinity (Kd = 65 nM) binding component was observed. Muscimol, thiomuscimol, tetrahydroisoxazole-5,4-c-pyridin-3-ol, imidazole acetic acid and bicuculline each competitively inhibited both high affinity and low affinity [3H]GABA binding. The potency of these inhibitors was similar to that reported for the GABA receptor from mammalian brain. It is concluded that the GABA receptor from catfish brain has very similar properties to the receptor from mammalian central nervous system and consequently has not undergone any obvious evolutionary changes.

Animals↗

PubMed2003

Pre- and post-synaptic mechanisms regulating the clustering of type A gamma-aminobutyric acid receptors (GABAA receptors).

Postsynaptic clustering of GABAA (type A gamma-aminobutyric acid) receptors is essential to ensure proper function of GABAergic synapses. This process is initiated during synapse formation and is maintained throughout life. The tubulin-associated protein gephyrin is required for clustering of GABAA receptors, but its specific role in this process is not understood. A second protein associated selectively with GABAA receptors at postsynaptic sites is dystrophin. It is present in a subset of GABAergic synapses along with several partners, forming the dystrophin-associated protein complex. In this review, we discuss recent advances in the role of neuronal activity and trans-synaptic signaling for the clustering of gephyrin and dystrophin during synaptogenesis and on the role of these proteins for plasticity and maintenance of mature synapses.

Animals↗

PubMed1996

Subcellular localization of gamma-aminobutyric acid type A receptors is determined by receptor beta subunits.

gamma-aminobutyric acid type A (GABAA) receptors are the major sites of fast synaptic inhibition in the brain. They are constructed from four subunit classes with multiple members: alpha (1-6), beta (1-4), gamma (1-4), and delta (1). The contribution of subunit diversity in determining receptor subcellular targeting was examined in polarized Madin-Darby canine kidney (MDCK) cells. Significant detection of cell surface homomeric receptor expression by a combination of both immunological and electrophysiological methodologies was only found for the beta 3 subunit. Expression of alpha/beta binary combinations resulted in a nonpolarized distribution for alpha 1 beta 1 complexes, but specific basolateral targeting of both alpha 1 beta 2 and alpha 1 beta 3 complexes. The polarized distribution of these alpha/beta complexes was unaffected by the presence of the gamma 2S subunit. Interestingly, delivery of receptors containing the beta 3 subunit to the basolateral domain occurs via the apical surface. These results show that beta subunits can selectively target GABAA receptors to distinct cellular locations. Changes in the spatial and temporal expression of beta-subunit isoforms may therefore provide a mechanism for relocating GABAA receptor function between distinct neuronal domains. Given the critical role of these receptors in mediating synaptic inhibition, the contribution of different beta subunits in GABAA receptor function, may have implications in neuronal development and for receptor localization/clustering.

Animals↗

PubMed1997

Directing gene expression to cerebellar granule cells using gamma-aminobutyric acid type A receptor alpha6 subunit transgenes.

Expression of the gamma-aminobutyric acid type A receptor alpha6 subunit gene is restricted to differentiated granule cells of the cerebellum and cochlear nucleus. The mechanisms underlying this limited expression are unknown. Here we have characterized the expression of a series of alpha6-based transgenes in adult mouse brain. A DNA fragment containing a 1-kb portion upstream of the start site(s), together with exons 1-8, can direct high-level cerebellar granule cell-specific reporter gene expression. Thus powerful granule cell-specific determinants reside within the 5' half of the alpha6 subunit gene body. This intron-containing transgene appears to lack the cochlear nucleus regulatory elements. It therefore provides a cassette to deliver gene products solely to adult cerebellar granule cells.

Animals↗

PubMed1993

Drosophila gamma-aminobutyric acid receptor gene Rdl shows extensive alternative splicing.

The Drosophila gamma-aminobutyric acid (GABA) receptor subunit gene Rdl was isolated on the basis of a mutant phenotype showing high levels of insensitivity to picrotoxinin and cyclodiene insecticides. Following analysis of two dissimilar cDNAs isolated from the locus, we report that Rdl undergoes extensive alternative splicing at two locations in the putative extracellular domain. At each location a choice is made between exons of the same size: "a" or "b" (23 amino acids long with two substitutions) and "c" or "d" (46 residues long with 10 substitutions). The function of these alternative exons remains unclear; however, exon d contains a putative site for casein kinase II phosphorylation. All possible combinations of exons (a with c or d and b with c or d) were found in RNA isolated from early embryos. This is the first demonstration of alternative splicing in a GABA receptor gene from invertebrates.

Alternative Splicing↗

PubMed2001

Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux.

Inhibitory gamma-aminobutyric acid (GABA)(A) receptors are subject to modulation at a variety of allosteric sites, with pharmacology dependent on receptor subunit combination. The influence of different alpha subunits in combination with beta3gamma2s was examined in stably expressed human recombinant GABA(A) receptors by measuring (36)Cl influx through the ion channel pore. Muscimol and GABA exhibited similar maximal efficacy at each receptor subtype, although muscimol was more potent, with responses blocked by picrotoxin and bicuculline. Receptors containing the alpha3 subunit exhibited slightly lower potency. The comparative pharmacology of a range of benzodiazepine site ligands was examined, revealing a range of intrinsic efficacies at different receptor subtypes. Of the diazepam-sensitive GABA(A) receptors (alpha1, alpha2, alpha3, alpha5), alpha5 showed the most divergence, being discriminated by zolpidem in terms of very low affinity, and CL218,872 and CGS9895 with different efficacies. Benzodiazepine potentiation at alpha3beta3gamma2s with nonselective agonist chlordiazepoxide was greater than at alpha1, alpha2, or alpha5 (P < 0.001). The presence of an alpha4 subunit conferred a unique pharmacological profile. The partial agonist bretazenil was the most efficacious benzodiazepine, despite lower alpha4 affinity, and FG8205 displayed similar efficacy. Most striking were the lack of affinity/efficacy for classical benzodiazepines and the relatively high efficacy of Ro15-1788 (53 +/- 12%), CGS8216 (56 +/- 6%), CGS9895 (65 +/- 6%), and the weak partial inverse agonist Ro15-4513 (87 +/- 5%). Each receptor subtype was modulated by pentobarbital, loreclezole, and 5alpha-pregnan-3alpha-ol-20-one, but the type of alpha subunit influenced the level of potentiation. The maximal pentobarbital response was significantly greater at alpha4beta3gamma2s (226 +/- 10% increase in the EC(20) response to GABA) than any other modulator. The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3.

Allosteric Regulation↗

PubMed1992

Regulatory influences on the production of gamma-aminobutyric Acid by a marine pseudomonad.

A pseudomonad capable of producing gamma-aminobutyric acid (GABA) was isolated from seawater via an enrichment in which glutamate was the sole carbon and nitrogen source. The organism grew optimally at pH 7.3 and at 25 degrees C. Putrescine, alanine, and glucose-nitrate also served as effective growth substrates. The isolate grew poorly on GABA. Cell suspensions of the organism in 0.02 M phosphate buffer (pH 7.6) containing NaCl (19.4 g liter) and MgCl(2). 6H(2)O(3 g liter) produced GABA from succinic semialdehyde in combination with glutamate or alanine but not from any substrate alone. Little or no GABA was produced with putrescine or glucose-nitrate as substrates. GABA production in the amino acid cosubstrate systems was transitory with optimum levels occurring in the suspension fluid after 3 h of incubation (0.3 and 0.03 mM for glutamate and alanine cosubstrates, respectively). However, yields of GABA in the cell suspension fluid were low, and quantities near that predicted from stoichiometry could be obtained only by extracting cell suspensions with methanol. GABA release in the suspension fluid was increased with higher pH or by decreasing NaCl. Substitution of the salt by the equivalent Tris-HCl or KCl likewise resulted in increased GABA release. When nigericin (10 mug ml) was added to cell suspensions in which NaCl was not decreased, GABA release increased in a way similar to that observed in suspensions with decreased NaCl. The ionophore also decreased GABA uptake by cell suspensions of GABA-grown cells, and the effect was duplicated by lowering NaCl in cell suspensions. The results indicate a role for an Na-dependent transport system in GABA release.

Journal Article↗

PubMed2001

Fipronil modulation of gamma-aminobutyric acid(A) receptors in rat dorsal root ganglion neurons.

The gamma-aminobutyric acid (GABA) receptor is an important site of action of a variety of chemicals, including barbiturates, benzodiazepines, picrotoxin, bicuculline, general anesthetics, alcohols, and certain insecticides. Fipronil is the first phenylpyrazole insecticide introduced for pest control. It is effective against some insects that have become resistant to the existing insecticides. To elucidate the mechanism of fipronil interaction with the mammalian GABA system, whole-cell patch-clamp experiments were performed using rat dorsal root ganglion neurons in primary culture. Fipronil suppressed the GABA-induced whole-cell currents reversibly in both closed and activated states. The IC(50) values and Hill coefficients for fipronil block of the GABA(A) receptor were estimated to be 1.66 +/- 0.18 microM and 1.23 +/- 0.14 for the closed receptor, respectively, and 1.61 +/- 0.14 microM and 0.96 +/- 0.06 for the activated receptor, respectively. The association rate and dissociation rate constants of fipronil effect were estimated to be 673 +/- 220 M(-1) s(-1) and 0.018 +/- 0.0035 s(-1) for the closed GABA(A) receptor, respectively, and 6600 +/- 380 M(-1) s(-1) and 0.11 +/- 0.0054 s(-1) for the activated GABA(A) receptor, respectively. Thus, both the association and dissociation rate constants of fipronil for the activated GABA(A) receptor are approximately 10 times as large as those for the closed receptor. Experiments with coapplication of fipronil and picrotoxinin indicated that they did not compete for the same binding site to block the receptor. It is concluded that although fipronil binds to the GABA(A) receptor without activation, channel opening facilitates fipronil binding to and unbinding from the receptor.

Animals↗

PubMed1994

Impact of beta and gamma variants on ligand-binding properties of gamma-aminobutyric acid type A receptors.

We expressed in cultured cells recombinant gamma-aminobutyric acid type A (GABAA) receptors of the subunit compositions alpha 1 beta j gamma k and alpha 5 beta j gamma k (j = 1, 2, or 3 and k = 2 or 3). A comparison of ligand-binding properties revealed a functional role for individual beta variants, which depended on the alpha subunit in the GABAA receptor. Recombinant alpha 5 beta x gamma 2/3 receptors recognized the cage convulsant t-butylbicyclophosphoro[35S]thionate, as well as the benzodiazepine (BZ) receptor inverse agonist [3H]Ro 15-4513, only with the beta 3 variant. In contrast, the exchange of beta variants in alpha 1 beta x gamma 2 receptors imparted differential modulation of t-butyl-bicyclophosphoro[35S]thionate binding by BZ receptor ligands. The BZ site of gamma 3-containing receptors was partially independent of the accompanying alpha and beta variants. alpha 1/5 beta 3 gamma 3 receptors were zolpidem insensitive but distinguished from alpha 5 beta 3 gamma 2 receptors by high affinity for the partial BZ receptor agonist CI 218,872. The distinct affinities of recombinant receptors for CI 218,872 suggested that the alpha 5 beta 3 gamma 2 receptor is the dominant zolpidem-insensitive GABAA receptor in the brain. Hence, alpha 5 beta 3 gamma 3 recpetors are not a major fraction of the native zolpidem-insensitive receptors, even though their genes are colocalized on mouse chromosome 7 and on human chromosome 15.

Azides↗

PubMed2005

Gama-aminobutyric acid accumulation in Elsholtzia splendens in response to copper toxicity.

A solution with different Cu supply levels was cultured to investigate gama-aminobutyric acid (GABA) accumulation in Elsholtzia splendens, a native Chinese Cu-tolerant and accumulating plant species. Increasing Cu from 0.25 to 500 micromol/L significantly enhanced levels of GABA and histidine (His), but considerably decreased levels of aspartate (Asp) and glutamate (Glu) in the leaves. The leaf Asp level negatively correlated with leaf Cu level, while leaf GABA level positively correlated with leaf Cu level. The leaf Glu level negatively correlated with leaf GABA level in Elsholtzia splendens. The depletion of leaf Glu may be related to the enhanced synthesis of leaf GABA under Cu stress.

Copper↗

PubMed1990

[The effect of gamma-aminobutyric acid at the somatic and dendritic level in Purkinje cells in the cerebellum of the frog in vitro].

The effect of gamma-aminobutyric acid (GABA) on its receptors localized on the somatic and dendritic membrane of Purkinje cells was tested on the isolated cerebellum of the frog. The action of GABA was found to be different in the two zones studied. On the membrane of the cell bodies GABA inhibited the overall synaptic potential and spontaneous activity by a mechanism dependent on increased Cl- conductivity resulting in hyperpolarization of the somatic membrane. On the dendritic membrane the inhibitory effect of GABA on the spontaneous activity of dendrites was only minimal and shortlasting. At intradendritic recording a depolarizing effect of GABA was observed whose mechanism is so far unknown.

Action Potentials↗

PubMed1984

Modulation by calcium of gamma-aminobutyric acid (GABA) binding to GABAA and GABAB recognition sites in rat brain. Involvement of different mechanisms.

Calcium modulates sodium-independent binding of gamma-aminobutyric acid (GABA) to GABAA and GABAB recognition sites located in synaptic membranes of rat brain. At 37 degrees the binding of [3H]GABA to the GABAB recognition site is dramatically stimulated by Ca2+ with an EC50 (half-saturation constant) of congruent to 10 microns, whereas the binding to the GABAA recognition site is only slightly, but significantly, potentiated by Ca2+ with an EC50 of congruent to 0.1-1.0 micron. The effect of calcium on GABAA recognition sites requires a temperature of 37 degrees and the presence of calmodulin. Only GABAA recognition sites are linked to benzodiazepine recognition sites, and the interaction between these sites is modulated by Ca2+ at physiological ion concentrations. When free Ca2+ in the assay medium is below 10 nM, only one population of low-affinity GABAA recognition sites can be measured; however, when free Ca2+ is at the micromolar level, or if diazepam is present, a high affinity-binding site appears in addition to the pre-existing low-affinity component. On the basis of affinity there is a single population of GABAB bindings sites, but the number of sites is about 90% greater at 37 degrees than at 4 degrees. This temperature-dependent increase in the number of GABAB recognition sites is calmodulin-independent, and data with leupeptin, hemin, and antipain suggest that this temperature-dependent increase in GABAB sites might involve the activity of Ca2+-dependent protease(s).

Animals↗

PubMed1989

Characterization of gamma-aminobutyric acid and dopamine overflow following acute implantation of a microdialysis probe.

The present study characterized the voltage and calcium dependence of gamma-aminobutyric acid and dopamine overflow after the acute implantation of a microdialysis probe. Probes were implanted in dorsolateral striatum and globus pallidus. Experiments were performed under light halothane anesthesia. Basal, extracellular levels of GABA were not affected by tetrodotoxin (TTX) and were increased to 140 percent of basal values by calcium free Ringer. Basal, extracellular levels of dopamine were reduced to 14 percent of basal values by the addition of TTX and to 30 percent of basal values by the removal of calcium from the Ringer solution. The results suggest that in this in vivo preparation basal extracellular dopamine is largely of vesicular origin while GABA is not.

Animals↗

PubMed1991

Release of glutamate and gamma-aminobutyric acid in the ovine fetal hippocampus: ontogeny and effect of hypoxia.

The effects of increased potassium ion concentration (50 mM) and hypoxia on the efflux of glutamate and gamma-aminobutyric acid (GABA) were studied in ovine fetal hippocampal slices using the static-pool-interface superfusion method at three selected gestational ages (85 days, 105 days, 135 days; term, about 147 days). There was no difference in spontaneous efflux of either amino acid across the three gestational ages. Potassium ion stimulated the efflux of glutamate in the hippocampus of the 85-days-old fetus only, and this efflux of glutamate was not calcium-ion dependent. Potassium ion stimulated the efflux of GABA in the ovine fetal hippocampus at days 85 and 105 only; this efflux was calcium-ion dependent. A ten-minute period of hypoxia did not enhance the efflux of either glutamate or GABA. The data indicate that both glutamate and GABA are present in the ovine fetal hippocampus, and can be released by depolarizing concentrations of potassium ion in the immature fetus. The lack of potassium ion-evoked efflux of glutamate and GABA in the mature fetal hippocampus may reflect a toxic response to this stimulus. The lack of calcium ion regulation of glutamate efflux compared with GABA efflux indicates either a difference in maturation of glutamatergic synaptic mechanisms compared with GABAergic mechanisms, or is indicative of glial release of glutamate. Prolonged, severe hypoxia (greater than 10 min) may be required to evoke efflux of glutamate in the developing fetal hippocampus.

Animals↗