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At least 487 records · Page 27Linked to original sources
PubMed1992

Identification of the cAMP-dependent protein kinase and protein kinase C phosphorylation sites within the major intracellular domains of the beta 1, gamma 2S, and gamma 2L subunits of the gamma-aminobutyric acid type A receptor.

Gamma-aminobutyric acid Type A (GABAA) receptors are the major sites of synaptic inhibition in the central nervous system. These receptors are thought to be pentameric complexes of homologous transmembrane glycoproteins. Molecular cloning has revealed a multiplicity of different GABAA receptor subunits divided into five classes, alpha, beta, gamma, delta, and rho, based on sequence homology. Within the proposed major intracellular domain of these subunits, there are numerous potential consensus sites for protein phosphorylation by a variety of protein kinases. We have used purified fusion proteins of the major intracellular domain of GABAA receptor subunits produced in Escherichia coli to examine the phosphorylation of these subunits by cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). The purified fusion protein of the intracellular domain of the beta 1 subunit was an excellent substrate for both PKA and PKC. PKA and PKC phosphorylated the beta 1 subunit fusion protein on serine residues on a single tryptic phosphopeptide. Site-directed mutagenesis of serine 409 in the intracellular domain of the beta 1 subunit to an alanine residue eliminated the phosphorylation of the beta 1 subunit fusion protein by both protein kinases. The purified fusion proteins of the major intracellular domain of the gamma 2S and gamma 2L subunits of the GABAA receptor were rapidly and stoichiometrically phosphorylated by PKC but not by PKA. The phosphorylation of the gamma 2S subunit occurred on serine residues on a single tryptic phosphopeptide. Site-directed mutagenesis of serine 327 of the gamma 2S subunit fusion protein to an alanine residue eliminated the phosphorylation of the gamma 2S fusion protein by PKC. The gamma 2L subunit is an alternatively spliced form of the gamma 2S subunit that differs by the insertion of 8 amino acids (LLRMFSFK) within the major intracellular domain of the gamma 2S subunit. The PKC phosphorylation of the gamma 2L subunit occurred on serine residues on two tryptic phosphopeptides. Site-specific mutagenesis of serine 343 within the 8-amino acid insert to an alanine residue eliminated the PKC phosphorylation of the novel site in the gamma 2L subunit. No phosphorylation of a purified fusion protein of the major intracellular loop of the alpha 1 subunit was observed with either PKA or PKC. These results identify the specific amino acid residues within GABAA receptor subunits that are phosphorylated by PKA and PKC and suggest that protein phosphorylation of these sites may be important in regulating GABAA receptor function.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Sampling extracellular aspartate, glutamate and gamma-aminobutyric acid in striate cortex of awake cat by in vivo microdialysis: surgical and methodological aspects.

A method which permits repeated microdialysis in the cortical layers of area 17 of the awake cat is described. Under visual control through a surgical microscope and using a stereotactic instrument, four probe guides are permanently implanted in area 17 of one hemisphere of the anesthetized animal and two fixation bars are mounted on the skull to allow fixation of the cat in a stereotactic frame. The implantation of four probe guides in the same hemisphere allows simultaneous sampling from different cortical regions serving different parts of the visual field. A removable transparent cover protects the probe guides. After recovery from surgery the awake cats are trained to adapt to a fixation of 5 h in a stereotaxic apparatus. Once adapted to that situation, the cats are ready for microdialysis experiments without anesthesia. The day of the experiment, the awake animal was fixed in the stereotactic frame and the probes inserted into the guides. To test the validity of the method, the basal efflux and the depolarization efflux, triggered by the addition of 65 mM K(+) to the artificial cerebrospinal fluid, of the amino acids aspartate, glutamate and gamma-aminobutyric acid are measured by two HPLC-electrochemical detection methods. The exact localization of the probes and the reaction of the surrounding tissue is studied using immunocytochemistry for glutamate and glial fibrilary acidic protein. Our neurochemical and morphological results suggest the feasibility of multiple and repeated probe insertions for microdialysis experiments in the cerebral cortex of awake and behaving cat. This method provides a new tool to investigate the cortical plasticity.

Animals↗
PubMed2007

Compensation by reduced L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses in a mouse model with reduced gamma-aminobutyric acid type A receptor-mediated synaptic inhibition.

L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists increase the threshold for electroshock-induced convulsions. Here, we show that a transgenic mouse line overexpressing cerebellum-restricted gamma-aminobutyric acid type A (GABA(A)) receptor alpha6 subunit in the hippocampal CA1 pyramidal cells (Thy1alpha6 mouse line) exhibits about a 20% increase in the electroshock current intensity inducing tonic hindlimb extension convulsion in 50% of the mice compared with that of their wild-type controls. AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in patch clamp recordings of CA1 pyramidal neurons in hippocampal slices had decreased amplitudes (8.4 +/- 2.2 pA) in the transgenics compared with the wild types (10.3 +/- 2.5 pA) but showed no change in current decay or frequency. Our results suggest that decreased AMPA-mediated neurotransmission might explain the increased threshold for electroconvulsions and warrant further studies on the regulation between various components of inhibition and excitation in neurons.

Animals↗
PubMed1974

Gamma-aminobutyric acid effects on pituitary gonadotropin secretion.

Gamma-aminobutyric acid (GABA) injected into the third ventricle of male rats promotes the release of pituitary luteinizing hormone (LH) but not follicle-stimulating hormone. When GABA was injected directly into the pituitary it was ineffective in promoting LH release. This evidence suggests that GABA may play a role in controlling the discharge of hypothalamic luteinizing hormone releasing factor.

Aminobutyrates↗
PubMed1986

Purification and identification of the functional sodium- and chloride-coupled gamma-aminobutyric acid transport glycoprotein from rat brain.

Using the reconstitution conditions developed recently (Radian, R., and Kanner, B. I. (1985) J. Biol. Chem. 260, 11859-11865) we have now purified the sodium- and chloride-coupled gamma-aminobutyric acid transporter from rat brain to apparent homogeneity. A partially purified transporter preparation was passed over wheat germ agglutinin-Sepharose 6MB and non-bound proteins were washed away. The transport activity, as expressed upon reconstitution of the protein into liposomes, was eluted by a solution containing Triton X-100 and N-acetylglucosamine. The specific transport activity was increased almost 400-fold over that of the crude extract. Taking into account an approximately 2.5-fold inactivation during the lectin column chromatography, the actual purification is about 1000-fold. Sodium dodecyl sulfate-polyacrylamide electrophoresis of the active fractions revealed one band of 80 kDa and small amounts of a band which ran at an apparent molecular mass of 160 kDa. The ratio between the two could be experimentally changed such as, for instance, by lyophilization. Polyclonal antibodies were prepared against the 80-kDa band which also cross-reacted with the 160-kDa band, indicating that the latter apparently represents a dimer form of the first. Using Protein A-Sepharose Cl-4B and the antibody against the 80-kDa band, we were able to quantitatively immunoprecipitate the potential gamma-aminobutyric acid transport activity from a crude transporter preparation. The pure transporter preparation exhibited the same features of the transporter in synaptic plasma membrane vesicles, namely dependence on sodium and chloride, electrogeneity, affinity, and efflux and exchange properties. We conclude that the 80-kDa band represents the gamma-aminobutyric acid transporter.

Animals↗
PubMed1979

Stimulation of benzodiazepine receptor binding by gamma-aminobutyric acid.

The effect of the neurotransmitter gamma-aminobutyric acid (GABA) on high-affinity binding of benzodiazepines to brain membranes has been investigated. GABA stimulated [3H]diazepam binding by more than 100% when extensively washed membranes from brain tissue were used. This GABA-stimulated benzodiazepine binding occurred in all brain regions examined. The stimulation was specific for GABA agonist. It was inhibited by the GABA receptor blocker bicuculline methiodide. A large number of compounds structurally closely related to GABA but without direct effect on the GABA receptor failed to enhance [3H]diazepam binding. The stimulation of benzodiazepine binding was caused by an increase in affinity; the number of binding sites remained unchanged. Half-maximal activation of [3H]diazepam binding occurred in the presence of 300 nM muscimol or 900 nM GABA. beta-Guanidinopropionic acid and imidazoleacetic acid were much weaker activators. It is suggested that the described stimulation of benzodiazepine high-affinity binding is mediated by a receptor for GABA. This site of GABA action exhibits different properties when compared to GABA receptors, as characterized by high-affinity binding of GABA agonists.

Animals↗
PubMedDate not supplied

Preparation and properties of 99mTc(CO)3+-labeled N,N-bis(2-pyridylmethyl)-4-aminobutyric acid.

Labeling biomolecules with (99m)Tc(CO)(3)(+) ((99m)Tc tricarbonyl) is attracting increasing attention. Although histidine is often considered an ideal bifunctional chelator for (99m)Tc (or (188)Re) tricarbonyl, the family of dipicolylamine carboxylate chelators may be a useful alternative because of the expected ease of synthesis and because the structure provides a pendent carboxylate for potential conjugation to biomolecules. The dipicolylamine chelator N,N-bis(2-pyridylmethyl)-4-aminobutyric acid (BPABA) was synthesized using 4-aminobutyric acid in place of glycine or aminopropionic acid in the literature, to avoid possible involvement of the carboxylate in the complex formation process by forming five- or six-membered chelation rings. Using a commercial tricarbonyl kit (Mallinckrodt), the complex formation properties of both BPABA and commercial histidine with (99m)Tc tricarbonyl were investigated, and the in vitro complex stabilities in saline and in serum were compared. Stability in vivo was also examined following i.v. administration to normal mice. BPABA was synthesized simply and quantitatively by reacting picolyl chloride with aminobutyric acid in one step. On RP HPLC, the product eluted essentially in one peak and the structure was confirmed by ESI-MS. After labeling, both BPABA and histidine were shown by RP HPLC to form tricarbonyl complexes. In both cases, after incubation at 100 degrees C for 20 min, only one predominant peak of (99m)Tc(CO)(3)(+)-histidine or (99m)Tc(CO)(3)(+)-BPABA was apparent, and both complexes were stable at room temperature in saline for at least 24 h. After incubation for 24 h in 37 degrees C serum, by SE HPLC, 20% of the (99m)Tc(CO)(3)(+)-histidine was bound to serum protein compared to less than 10% for (99m)Tc(CO)(3)(+)-BPABA. A 5000 molar excess of histidine at 100 degrees C for 6 h was unable to dissociate (99m)Tc(CO)(3)(+)-BPABA. By contrast, BPABA easily dissociated (99m)Tc(CO)(3)(+)-histidine under the same conditions. Both complexes were stable in vivo in mice, and (99m)Tc(CO)(3)(+)-BPABA showed rapid and specific hepatobiliary clearance while (99m)Tc(CO)(3)(+)-histidine was cleared through the kidneys. In conclusion, BPABA was easily synthesized and was shown to possess properties comparable to histidine for labeling of biomolecules with (99m)Tc tricarbonyl. However, it was found that the chelator concentration required for quantitative (99m)Tc tricarbonyl labeling with both BPABA and histidine were 2 orders higher than that required with more conventional labeling using MAG(3). Finally, the complex (99m)Tc(CO)(3)(+)-BPABA itself was found to clear exclusively via the hepatobiliary pathway and may have value as a potential hepatobiliary imaging agent.

Aminobutyrates↗
PubMed1990

Changes in gamma-aminobutyric acid, mu-opioid and neurotensin receptors in the accumbens-pallidal projection after discrete quinolinic acid lesions in the nucleus accumbens.

Discrete quinolinic acid lesions in the nucleus accumbens altered [3H]muscimol binding to gamma-aminobutyric acid receptors, [125I]neurotensin binding to neurotensin receptors, [125I]Tyr-D-Ala-Gly-NMePHe-Gly-OH binding to mu-opioid receptors, and [3H]quinuclidinyl benzilate binding to muscarinic receptors. Within lesions of the lateral accumbens core, [3H]muscimol binding increased and [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH, [125I]neurotensin and [3H]quinuclidinyl benzilate binding decreased. Lesions of the medial nucleus accumbens resulted in decreased [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH and [3H]quinuclidinyl benzilate binding while no alterations were observed for [3H]muscimol or [125I]neurotensin binding. These data support anatomical distinctions between medial and lateral nucleus accumbens. Destruction of intrinsic neurons in the dorsomedial nucleus accumbens core increased [3H]muscimol binding in the dorsal rim of the ventral pallidum and the rostral globus pallidus without altering [125I]Tyr-D-Ala-Gly-NMePhe-Gly-OH binding. Destruction of neurons in the lateral nucleus accumbens core or medial shell did not alter [3H]muscimol binding in the ventral pallidum. The lack of upregulation in gamma-aminobutyric acid receptors suggests that the gamma-aminobutyric acid-containing projection from the dorsomedial core to the dorsal rim of the ventral pallidum differs from the projection from the lateral accumbens core and medial shell to the more ventral regions of the pallidum. Fluoro-gold retrograde tracer histochemistry confirmed the specific projection from the dorsomedial core to the dorsal ventral pallidum; and from the shell of the nucleus accumbens to more ventral regions of the ventral pallidum.

Animals↗
PubMed2000

A role of nitric oxide as an inhibitor of gamma-aminobutyric acid transaminase in rat brain.

The present study has been aimed to investigate the effect of nitric oxide (NO) on the concentration of gamma-aminobutyric acid (GABA) in rat brain. The concentrations of GABA and glutamate and the activities of glutamic acid decarboxylase (GAD) and gamma-aminobutyric acid transaminase (GABA-T) were determined in groups of animals 5 and 30 min after intraperitoneal injection of a NO-increasing dose (1,000 mg/kg) of its precursor, L-arginine and a dose (50 mg/kg) of N-nitro-L-arginine methyl ester (L-NAME) that inhibits NO synthesis from L-arginine. L-arginine-induced elevation of NO concentration was accompanied by an increased concentration of GABA in the brain. GABA-T activity was inhibited in these animals. NO-decreasing action of L-NAME coincided with a reduction in the concentration of GABA and an enhancement of GABA-T activity. Both L-arginine and L-NAME did not alter the activity of GAD and the concentration of glutamate. An interpretation of these data suggests that NO has a GABA-T-inhibiting role in the brain.

4-Aminobutyrate Transaminase↗
PubMed1992

gamma-Aminobutyric acid immunoreactive structures in the nucleus tractus solitarius: a light and electron microscopic study.

gamma-Aminobutyric acid immunoreactive perikarya and boutons in the nucleus tractus solitarius of the cat were examined at both the light and electron microscopic level. Immunoreactive neurones were found predominantly in the parvocellular subdivision of the nucleus tractus solitarius and to a lesser degree in all the other subdivisions of the nucleus tractus solitarius and the dorsal vagal motonucleus. All the immunoreactive perikarya observed were similar in size and morphology. gamma-Aminobutyric acid immunoreactive boutons were observed throughout the nucleus tractus solitarius. However, in contrast to its high content of immunoreactive perikarya the parvocellular subdivision contained the lowest density of immunoreactive boutons. Ultrastructural examination of immunoreactive boutons in the different regions of the nucleus tractus solitarius revealed that they formed synaptic specializations, predominantly with dendritic shafts, all of which were of the symmetric type. This pattern of innervation was observed throughout the medial, commissural, ventrolateral and parvocellular subdivisions of the nucleus tractus solitarius.

Animals↗
PubMed1986

Immunocytochemical localization of gamma-aminobutyric acid in the rat hippocampal formation.

gamma-Aminobutyric acid (GABA) was detected immunocytochemically in the rat hippocampal formation utilizing a new antiserum made against GABA conjugated to bovine serum albumin. GABA immunoreactivity was found to be concentrated in pericellular networks of fibers around both dentate granule and hippocampal pyramidal neurons. Ultrastructural analysis indicated that GABA-immunoreactive (IR) terminals most often contained small clear vesicles and made symmetrical contacts with somata and dendritic shafts of hippocampal neurons. In addition, numerous GABA-IR neurons resembled basket interneurons that have been described in previous reports.

Animals↗
PubMedDate not supplied

Hypotensive and postural effects of the gamma-aminobutyric acid agonist muscimol and of clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, have been shown to reduce blood pressure by a centrally mediated mechanism. The present series of experiments compared cardiovascular responses to muscimol with those of clonidine in anesthetized and conscious spontaneously hypertensive rats. Both agents given intraventricularly reduced blood pressure, heart rate, and spontaneous sympathetic outflow in anesthetized animals. Muscimol also produced marked hypotension in conscious rats. However, compensatory adjustments to upright tilt were inhibited only slightly at most by both agents, even at high doses. Therefore, muscimol, like other centrally acting hypotensive agents, appears to inhibit the sympathetic nervous system selectively.

Animals↗
PubMed1979

Action of gamma-aminobutyric acid on hypothalamo-neurohypophysial axons.

gamma-Aminobutyric acid (GABA) and the related compound, muscimol, were bath-applied to a preparation containing the rat median eminence, pituitary stalk and neurohypophysis, and are shown to reversibly reduce the amplitude, and increase the latency, of the antidromic compound action potential recorded from hypothalamoneurohypophysial axons in response to electrical stimulation of the posterior pituitary lobe. Both actions were antagonized by bicuculline, but were unaffected by strychnine. The data suggest that the peptidergic axons of the hypothalamo-neurohypophysial tract are endowed with receptors for GABA, which is believed to be synthesized and released by neurohypophysial glial cells.

Animals↗
PubMed1976

Cerebrospinal fluid gamma-aminobutyric acid in neurologic disease.

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.

Aminobutyrates↗
PubMed2003

Production of the secondary metabolites gamma-aminobutyric acid and monacolin K by Monascus.

gamma-Aminobutyric acid (GABA), a hypotensive agent, and monacolin K, a cholesterol-lowering drug, can be produced by Monascus spp. Under optimal culture conditions, the products of fermentation using Monascus spp. may serve as a multi-functional dietary supplement and can prevent heart disease. In this study, Monascus purpureus CCRC 31615, the strain with the highest amount of monacolin K, was identified from 16 strains using solid fermentation. Its GABA productivity was particularly high. Addition of sodium nitrate during solid-state fermentation of M. purpureus CCRC 31615 improved the productivity of monacolin K and GABA to 378 mg/kg and 1,267.6 mg/kg, respectively. GABA productivity increased further to 1,493.6 mg/kg when dipotassium hydrophosphate was added to the medium.

Anticholesteremic Agents↗
PubMed1999

Regulation of gamma-aminobutyric acid (GABA) transporters by extracellular GABA.

gamma-Aminobutyric acid (GABA) transporters on neurons and glia at or near the synapse function to remove GABA from the synaptic cleft. Recent evidence suggests that GABA transporter function can be regulated, although the initial triggers for such regulation are not known. One hypothesis is that transporter function is modulated by extracellular GABA concentration, thus providing a feedback mechanism for the control of neurotransmitter levels at the synapse. To test this hypothesis, GABA uptake assays were performed on primary dissociated rat hippocampal cultures that endogenously express GABA transporters and on mammalian cells stably expressing the cloned rat brain GABA transporter GAT1. In both experimental systems, extracellular GABA induces chronic changes in GABA transport that occur in a dose-dependent and time-dependent manner. In addition to GABA, ACHC and nipecotic acid, both substrates of GAT1, up-regulate transport; GAT1 transport inhibitors that are not transporter substrates down-regulate transport. These changes occur in the presence of blockers of both GABAA and GABAB receptors, occur in the presence of protein synthesis inhibitors, and are not influenced by intracellular GABA. Surface biotinylation experiments reveal that the increase in transport is correlated with an increase in surface transporter expression. This increase in surface expression is due, at least in part, to a slowing of GAT1 internalization in the presence of extracellular GABA. These data suggest that the GABA transporter fine-tunes its function in response to extracellular GABA and would act to maintain a constant level of neurotransmitter at the synaptic cleft.

Animals↗
PubMedDate not supplied

Suppression of a somatosympathetic reflex by the gamma-aminobutyric acid agonist muscimol and by clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, reduce blood pressure and sympathetic outflow and inhibit the "carotid occlusion reflex." In contrast, muscimol exerted only marginal effects on postural reflexes in a prior study. The somatosympathetic reflex, i.e., potentials evoked in sympathetic nerves in response to sensory nerve stimulation, is a useful model for studying centrally acting drugs. Effects of muscimol on the reflex were examined in anesthetized normotensive rats. At doses which had previously been shown to reduce blood pressure but to produce only minimal attenuation of postural reflexes in conscious hypertensive rats, muscimol, administered intracerebroventricularly, reduced blood pressure and inhibited the somatosympathetic reflex in the present study. The time course of the evoked potential was not altered. Baroreceptor activation and intracerebroventricular clonidine also suppressed the reflex. The inhibitory effect of muscimol but not that of clonidine was prevented by pretreatment with the GABA antagonist bicuculline. Thus, the marked suppression of the somatosympathetic reflex by muscimol and by clonidine, in contrast to minimal effects on postural reflexes, point to the selectivity of their central inhibitory actions.

Animals↗