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At least 379 records · Page 21Linked to original sources
PubMed2006

Dual actions of enflurane on postsynaptic currents abolished by the gamma-aminobutyric acid type A receptor beta3(N265M) point mutation.

BACKGROUND: At concentrations close to 1 minimum alveolar concentration (MAC)-immobility, volatile anesthetics display blocking and prolonging effects on gamma-aminobutyric acid type A receptor-mediated postsynaptic currents. It has been proposed that distinct molecular mechanisms underlie these dual actions. The authors investigated whether the blocking or the prolonging effect of enflurane is altered by a point mutation (N265M) in the beta3 subunit of the gamma-aminobutyric acid type A receptor. Furthermore, the role of the beta3 subunit in producing the depressant actions of enflurane on neocortical neurons was elucidated. METHODS: Spontaneous inhibitory postsynaptic currents were sampled from neocortical neurons in cultured slices derived from wild-type and beta3(N265M) mutant mice. The effects of 0.3 and 0.6 mm enflurane on decay kinetics, peak amplitude, and charge transfer were quantified. Furthermore, the impact of enflurane-induced changes in spontaneous action potential firing was evaluated by extracellular recordings in slices from wild-type and mutant mice. RESULTS: In slices derived from wild-type mice, enflurane prolonged inhibitory postsynaptic current decays and decreased peak amplitudes. Both effects were almost absent in slices from beta3(N265M) mutant mice. At clinically relevant concentrations between MAC-awake and MAC-immobility, the anesthetic was less effective in depressing spontaneous action potential firing in slices from beta3(N265M) mutant mice compared with wild-type mice. CONCLUSION: At concentrations between MAC-awake and MAC-immobility, beta3-containing gamma-aminobutyric acid type A receptors contribute to the depressant actions of enflurane in the neocortex. The beta3(N265M) mutation affects both the prolonging and blocking effects of enflurane on gamma-aminobutyric acid type A receptor-mediated inhibitory postsynaptic currents in neocortical neurons.

Action Potentials↗
PubMed1959

Free beta-hydroxy-gamma-aminobutyric acid in brain.

By using the methods of paper chromatography and high-potential paper electrophoresis and by comparing the pattern of prepared extracts with that of synthesized beta-hydroxy-gamma-aminobutyric acid, we found that free beta-hydroxy-gamma-aminobutyric acid exists in the brains of mice, rabbits, cattle, and human beings.

Amino Acids↗
PubMed1996

Conservation of gamma-aminobutyric acid type A receptor alpha 6 subunit gene expression in cerebellar granule cells.

The gamma-aminobutyric acid type A receptor cDNAs encoding the alpha 6 subunit homologues from chicken and goldfish have been cloned and sequenced. These proteins exhibit 83 and 75% identity, respectively, to the rat alpha 6 polypeptide. In situ hybridization has demonstrated that, as in mammals, the avian and teleost fish alpha 6 subunit genes are predominantly expressed in cerebellar granule cells. Correspondingly, flunitrazepam-non-displaceable binding of [3H]Ro 15-4513 (a benzodiazepine partial inverse agonist), which is a major characteristic of gamma-aminobutyric acid type-A receptors that contain the alpha 6 polypeptide, is also mainly found for cerebellar granule cells of fish and chick. The conservation of this expression pattern suggests that gamma-aminobutyric acid type A receptors possessing the alpha 6 subunit are of fundamental importance for cerebellar function and that the corresponding gene regulatory elements, e.g., granule cell-specific enhancers, have also been conserved.

Amino Acid Sequence↗
PubMed1990

Ultrastructure and synaptology of neurons immunoreactive for gamma-aminobutyric acid in the myenteric plexus of the guinea pig small intestine.

Immunoreactivity for gamma-aminobutyric acid is located in one morphologically-defined class of nerve cell body in the myenteric plexus of the guinea pig small intestine. These are a subgroup of the Dogiel type I nerve cells, characterized by their lamellar dendrites, about 1 micron thick and flattened in the plane of the myenteric plexus, and one (or rarely two) long axonal process that extends to either the longitudinal or the circular muscle. At an ultrastructural level the dendrites were characterized by their open cytoplasm in which were scattered granular vesicles, pale mitochondria, Golgi apparatus and endoplasmic reticulum. A large proportion of the dendritic surface was in direct contact with the extra-ganglionic space. In the cell body region, which was away from the ganglion surface, the nucleus was surrounded by a thin rim of cytoplasm. The cytoplasmic features are quite distinct from those of Dogiel type II neurons but they were shared by many other non-immunoreactive neurons. Synaptic inputs, which were all non-immunoreactive, were found on the dendrites, cell bodies, axon hillocks and axons of the gamma-aminobutyric acid-immunoreactive neurons. The predominant vesicle type in the presynaptic elements was the small clear vesicle, 40-60 nm in diameter. Based on two gamma-aminobutyric acid-immunoreactive cells that were examined in serial section, about 40-50% of synapses are dendritic, 20-25% are somatic, and 30-35% are on the axon hillock or first 50-70 microns of the axon. No synapses formed by immunoreactive varicosities were found on non-immunoreactive neurons or in the neuropil of the myenteric ganglia. Moreover, the lamellar dendrites or soma of gamma-aminobutyric acid neurons were never presynaptic elements forming relationships with other elements in the ganglia. It is concluded that the gamma-aminobutyric acid reactive Dogiel type I neurons are motor neurons providing inputs to the circular and longitudinal muscle layers.

Animals↗
PubMed1997

Sorting of two polytopic proteins, the gamma-aminobutyric acid and betaine transporters, in polarized epithelial cells.

The gamma-aminobutyric acid transporter (GAT-1) isoform of the gamma-aminobutyric acid and the betaine (BGT) transporters exhibit distinct apical and basolateral distributions when introduced into Madin-Darby canine kidney cells (Pietrini, G., Suh, Y. J., Edelman, L., Rudnick, G., and Caplan, M. J. (1994) J. Biol. Chem. 269, 4668-4674). We have investigated the presence of sorting signals in their COOH-terminal cytosolic domains by expression in Madin-Darby canine kidney cells of mutated and chimeric transporters. Whereas truncated GAT-1 (DeltaC-GAT) maintained the original functional activity and apical localization, either the removal (DeltaC-myc BGT) or the substitution (BGS chimera) of the cytosolic tail of BGT generated proteins that accumulated in the endoplasmic reticulum. Moreover, we have found that the cytosolic tail of BGT redirected apical proteins, the polytopic GAT-1 (GBS chimera) and the monotopic human nerve growth factor receptor, to the basolateral surface. These results suggest the presence of basolateral sorting information in the cytosolic tail of BGT. We have further shown that information necessary for the exit of BGT from the endoplasmic reticulum and for the basolateral localization of the GBS chimera is contained in a short segment, rich in basic residues, within the cytosolic tail of BGT.

Amino Acid Sequence↗
PubMedDate not supplied

Gamma aminobutyric acid effect on acetylcholine level and metabolism in rat cerebral cortex.

Gamma aminobutyric acid injected into the lateral brain ventricle of white rats in doses of 0.6, 0.8 and 1.6 mg raised the level of acetylcholine and in doses of 0.2, 0.4, 0.6, 0.8 and 1.6 mg increased acetylcholine synthesis. The effects were greatest 15 minutes after injection. Gamma aminobutyric acid injected intraventricularly in doses of 0.6 mg increased the activity of choline acetyltransferase but had no effect on the activity of choline esterase.

Acetylcholine↗
PubMed1984

Gamma-aminobutyric acid stimulates the release of endogenous ascorbic acid from rat striatal tissue.

Gamma-aminobutyric acid (GABA) was found to induce the release of ascorbic acid from rat striatal homogenates and minces. This release was studied with the use of a rapid superfusion system with an on-line amperometric detector that monitors for the presence of easily oxidized substances (i.e., ascorbate, 3,4-dihydroxyphenylethylamine). The release was found to be calcium-independent and depolarization-dependent. This releasable pool of ascorbate could be replenished through nonstereospecific uptake. The releasing action of GABA was mimicked by the GABA agonist, muscimol, and was completely inhibited by the GABA antagonist, picrotoxin. The structural analogues of GABA, beta-alanine and gamma-hydroxybutyric acid, had no effect. These data indicate that ascorbate release is GABA-receptor mediated and synaptically localized.

Animals↗
PubMed2004

Expression of functional receptors by the human gamma-aminobutyric acid A gamma 2 subunit.

gamma-Aminobutyric acid A (GABA(A)) receptors are heteromeric membrane proteins formed mainly by various combinations of alpha, beta, and gamma subunits; and it is commonly thought that the gamma 2 subunit alone does not form functional receptors. In contrast, we found that cDNA encoding the gamma 2L subunit of the human GABA(A) receptor, injected alone into Xenopus oocytes, expressed functional GABA receptors whose properties were investigated by using the two-microelectrode voltage-clamp technique. GABA elicited desensitizing membrane currents that recovered after a few minutes' wash. Repetitive applications of GABA induced a "run-up" of GABA currents that nearly doubled the amplitude of the first response. The GABA currents inverted direction at about -30 mV, indicating that they are carried mainly by Cl(-) ions. The homomeric gamma 2L receptors were also activated by beta-alanine > taurine > glycine, and, like some types of heteromeric GABA(A) receptors, the gamma 2L receptors were blocked by bicuculline and were potentiated by pentobarbital and flunitrazepam. These results indicate that the human gamma 2L subunit is capable of forming fully functional GABA receptors by itself in Xenopus oocytes and suggest that the roles proposed for the various subunits that make up the heteromeric GABA(A) receptors in situ require further clarification.

Amino Acids↗
PubMed1979

Release of gamma-aminobutyric acid from isolated brain synaptosomes during semicarbazide-induced convulsions.

The in vivo effect of semicarbazide (SC) and aminoxyacetic acid (AOAA) upon gamma-aminobutyric acid (GABA) levels in the synaptosomal fraction, and GABA release from the same fraction were studied in the mouse. The convulsive dose of SC reduced the GABA content in synaptosomes, and when the convulsions were protected by pretreatment with AOAA, the reduced GABA content in synaptosomes rose to or above the normal level. Moreover, the SC treatment decreased the GABA releases from synaptosomes both in a Ca2+-free Ringer's solution and in a high K+ Ringer's solution. When the convulsions were protected by pretreatment with AOAA, the decreased GABA releases in both the conditions rose to or above the normal levels. Therefore, it is suggested that the decrease in GABA release from the nerve endings, because of the decrease of GABA content in the same compartment, is possibly an important factor in the onset of some kinds of convulsions.

Aminooxyacetic Acid↗
PubMed1999

Changes in cerebrospinal fluid monoamine metabolites, tryptophan, and gamma-aminobutyric acid during the 1st year of life in normal infants. comparison with victims of sudden infant death syndrome.

Cerebrospinal fluid (CSF) levels of 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, homovanillic acid, tryptophan, and gamma-aminobutyric acid were measured using high-performance liquid chromatography in 102 infants during the 1st year of life (preterm and term neonates included). CSF levels are expressed versus corrected age (postnatal days - preterm days) which reflects the stage of maturity of the central nervous system. These results are compared to those obtained in CSF of 53 victims of sudden infant death syndrome (SIDS). All components were significantly higher in SIDS than in the age-matched control group. This increase does not seem to be an artefact related to death. Indeed, under the same conditions concerning postmortem time interval before CSF sampling and analysis, the levels are not significantly higher in infants who died from a known pathology than in living infants. Moreover, in living infants as regards a pathology such as asphyxia or hypoventilation in comparison with SIDS, similar profiles are observed in some neurotransmitters or metabolites. Other studies are necessary to explore further neurotransmission systems in SIDS.

Age Factors↗
PubMed1976

Renal tubular reabsorption of taurine, gamma-aminobutyric acid (GABA) and beta-alanine studied by continuous microperfusion.

Renal tubular reabsorption of taurine, gamma-aminobutyric acid (GABA), and beta-alanine was studied in vivo et situ by continuous microperfusion of single proximal tubules of the rat. In each case, reabsorption was much slower than that for other amino acids that have been studied. With a concentration of 0.1 mmol/l in initial load was reabsorbed over perfusion distance of 3 mm. Taurine reabsorption saturated with only 2.17 mmol/l in initial perfusate. Assuming simple two-parameter kinetics, upper limits for Km of 0.54 mmol/l and forVmax of 0.59 pmol-cm-1--s-1 for tubular reabsorption of taurine were estimated. High (20 mmol/l) concentrations of taurine or beta-alanine in perfusate completely inhibited GABA reabsorption, but L-phenylalanine (20 mmol/l) had no significant effect. The results indicate that the three amino acids are reabsorbed slowly from the proximal tubule by what may be a common transport system. This system appears to have a high affinity but low capacity and to be different from other known renal tubular transport systems for amino acids.

Alanine↗
PubMed1981

Kinetics of and rate equations for the uptake of alpha-amino-isobutyric aicd and gamma-aminobutyric acid by mouse brain slices incubated in a glucose-free medium containing pyruvate as the energy source.

Mouse cerebrum slices were incubated in a medium containing pyruvate instead of glucose as the energy source. After a preincubation period alpha-aminoisobutyric acid (AIB) or gamma-aminobutyric acid (GABA) was added, and the rate of uptake by the slices was measured. AIB and GABA are taken up to above their concentration in the medium. Although influx is slower, the rate equation is the same as that for influx from a glucose medium; namely v = Vmax/1 x Kt/S) + kuS, where v = rate of uptake, S = concentration of AIB or GABA in the medium, and Vmax, Kt, and Ku are constants. The equation shows two parallel pathways for concentrative uptake, one saturable and one unsaturable. The uptake systems for AIB and GABA are qualitatively different. The maximum rate of uptake of AIB by the saturable component is the same in both media even though, in the pyruvate medium, AIB is bound less strongly to the 'carriers'. The maximum rate of uptake of GABA by the saturable component is less in the pyruvate medium although GABA is bound somewhat more strongly to the 'carriers'. The temperature coefficients of the kinetic parameters and their corresponding energies were determined for GABA. Going from glucose to pyruvate medium has little effect on the Arrhenius activation energy (Ea) associated with Vmax and the heat of reaction (delta H) associated with Kt but increases Ea associated with Ku by 1140%.

Aminoisobutyric Acids↗
PubMed1988

gamma-Aminobutyric acid function in the rat striatum is under the double influence of nigrostriatal dopaminergic and thalamostriatal inputs: two modes of regulation?

Glutamic acid decarboxylase (GAD), gamma-[3H]-aminobutyric acid [( 3H]GABA) high-affinity uptake into synaptosomes, and endogenous GABA content were measured in the rat striatum 2-3 weeks following 6-hydroxydopamine injection in the ipsilateral substantia nigra to destroy the nigrostriatal dopaminergic pathway and after kainic acid injection into the centromedial-parafascicular complex of the ipsilateral thalamus to lesion the thalamostriatal input. Both lesions resulted in apparent GAD increase concomitant with a decreased [3H]GABA uptake into striatal synaptosomes. GABA content was increased selectively following the dopaminergic lesion. Kinetic analysis of the uptake process for [3H]GABA showed selectively a decreased Vmax following the dopaminergic lesion; in animals with thalamic lesion, however, the change only concerned the Km, which showed a decreased affinity of the transport sites for [3H]GABA. Determination of Km and Vmax for GAD action on its substrate glutamic acid showed an increased affinity of GAD for glutamic acid in the case of the dopaminergic lesion without any change in Vmax, whereas the thalamic lesion resulted in GAD increase concomitant with a selective increase in Vmax. These data suggest that striatal GABA neurons are under the influence of nigrostriatal dopaminergic neurons which may reduce the GABA turnover, whereas the exact nature of the powerful control also revealed on these neurons following thalamic lesion remains to be determined. Both lesions induced adaptive neurochemical responses of striatal GABA neurons, possibly reflecting in the case of the dopaminergic deprivation an increased GABA turnover.

Animals↗
PubMed1990

Evidence for functionally distinct subclasses of gamma-aminobutyric acid receptors in rabbit retina.

gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian retina, where it serves many roles in establishing complex response characteristics of ganglion cells. We now provide biochemical and physiological evidence that at least three subclasses of GABA receptors (A1, A2, and B) contribute to different types of synaptic integration. Receptor binding studies indicate that approximately three-fourths of the total number of [3H]GABA binding sites in retina are displaced by the GABAA receptor antagonist, bicuculline, whereas one-fourth are displaced by the GABA-B receptor agonist, baclofen. GABAA receptors can be described by a three-site binding model with KD values of 19 nM, 122 nM, and 5.7 microM. Benzodiazepines and barbiturates potentiate binding to the GABAA site, which suggests that significant numbers of GABAA receptors are coupled to regulatory sites for these compounds and thus are classified as GABAA1 receptors. The response to pentobarbital appears to involve a conversion of low-affinity sites to higher-affinity sites, and is reflected in changes in the densities of sites at different affinities. Functional studies were used to establish which of the different receptor subclasses regulate release from cholinergic amacrine cells. Our results show that GABA suppresses light-evoked [3H]acetylcholine release via GABAA2 receptors not coupled to a benzodiazepine or barbiturate regulatory site, and enhances release via GABAB receptors. GABAA1 sites do not appear to control acetylcholine release in rabbit retina.

Acetylcholine↗
PubMed1982

Presynaptic gamma-aminobutyric acid receptors in the rat anococcygeus muscle and their antagonism by 5-aminovaleric acid.

1 The effects of gamma-aminobutyric acid (GABA) and related drugs on the isolated anococcygeus muscle of the rat were determined. 2 GABA caused a dose-related inhibition of the electrically-evoked twitch response. 3 The maximum response to GABA was a 56.8% depression of twitch response, with an EC50 of 0.68 microM. 4 (+/-)-Baclofen mimicked the effect of GABA (EC50 0.9 microM). (+)-Baclofen was more than 100 times less active than (--)-baclofen. 5 The response to GABA was unaffected by picrotoxin or bicuculline but was antagonized by 5-aminovaleric acid (0.5) mM). 6 Our results suggest that GABAB receptors are present on motor nerve terminals in the rat anococcygeus muscle and that 5-aminovaleric acid is an antagonist of these receptors.

Amino Acids↗