Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The whole-cell configuration of the patch clamp technique was used to study the effect of an intracellular increase in cAMP on the frequency of GABA-mediated miniature post synaptic currents (MPSCs) in neonatal rats from (P6 to P12) CA3 hippocampal neurons in slices. In the presence of tetrodotoxin (1 microM), and kynurenic acid (1 mM) to block ionotropic glutamatergic currents, forskolin, an activator of adenylate cyclase, markedly increased the frequency of MPSCs without affecting their amplitude or kinetics. The inactive forskolin analog, 1,9-dideoxyforskolin (30 microM), had no effect on the frequency of MPSCs. The effect of forskolin was prevented by the specific protein kinase A (PKA) antagonist Rp-cAMP (30 microM). It is concluded that stimulation of PKA potentiates spontaneous GABA release in immature hippocampal neurons.
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PMID:Protein kinase A-dependent increase in frequency of miniature GABAergic currents in rat CA3 hippocampal neurons. 778 66

We developed a novel method for immunoaffinity purification of gamma-aminobutyric acid (GABAB) receptor from bovine cerebral cortex using a monoclonal antibody, which specifically recognizes an 80-kDa GABA-binding protein (Nakayasu, H., Mizutani, H., Hanai, K., Kimura, H., and Kuriyama, K. (1992) Biochem. Biophys. Res. Commun. 182, 722-726). The GABA binding activity in the solubilized synaptic membrane preparation was adsorbed on the antibody-conjugated beads and was eluted as a single protein band of 80 kDa by an acidic buffer, pH 2.5. The purified preparation mimicked the GABAB receptor in its binding activity for GABA, baclofen (GABAB receptor agonist) and 2-hydroxysaclofen (a GABAB receptor antagonist). The purified preparation was reconstituted with partially purified GTP-binding protein and an adenylylcyclase preparation on a phospholipid membrane. On addition of GABA or baclofen to the reconstituted membrane, the adenylylcyclase activity was inhibited, and this inhibition was antagonized by 2-hydroxysaclofen. Moreover, this inhibition by GABA was not observed in a system reconstituted system without either the 80-kDa GABA-binding protein or the GTP-binding protein. These results are strong evidence that the 80-kDa antigenic protein is the GABAB receptor. This is the first report of the nearly complete purification of the GABAB receptor.
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PMID:Immunoaffinity purification and characterization of gamma-aminobutyric acid (GABA)B receptor from bovine cerebral cortex. 838 68

The GABAB receptor in brain is one of the GABA receptor subtypes, and has been found to be negatively coupled to adenylate cyclase and phosphatidylinositide turnover. This receptor easily solubilizes from cerebral synaptic membrane preparations by 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) in the presence of asolectin. GABAB receptor solubilized from bovine cerebral cortex was purified using baclofen-coupled affinity beads (baclofen-coupled Toyopearl beads). Using these procedures, almost pure GABAB receptor (80 KDa protein) was obtained in the affinity eluate. A monoclonal antibody has been also raised against the purified GABAB receptor. The antibody recognized a protein of about 80 KDa in bovine brain synaptic membrane. Immunoabsorbent agarose beads conjugated with the antibody were able to remove more than 90% of the baclofen suppressive GABA binding activity in the solubilized synaptic membrane, and this system was found to be useful for the immunoaffinity column chromatographic separation of GABAB receptor. Preliminary studies of immunohistochemical visualization of GABAB receptor in the rat cerebellum suggested that this receptor may be exclusively localized at the presynaptic site of GABAergic neurons.
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PMID:Cerebral GABAB receptor: proposed mechanisms of action and purification procedures. 838 34

Whole-cell voltage-clamp recordings were used to examine the unusual pharmacological properties of the electrical coupling between rod-driven horizontal cells in skate retina as revealed previously by receptive-field measurements (Qian & Ripps, 1992). The junctional resistance was measured in electrically coupled cell pairs that had been enzymatically isolated and maintained in culture; the typical value was about 19.92 M omega (n = 45), more than an order of magnitude lower than the nonjunctional membrane resistance. These data and the intercellular spread of the fluorescent dye Lucifer Yellow provide a good indication that skate horizontal cells are well coupled. The junctional conductance between cells was not modulated by the neurotransmitters dopamine (200 microM) or GABA (1 mM), nor was it affected by the membrane-permeable analogues of cAMP or cGMP, or the adenylate cyclase activator, forskolin. Although resistant to agents that have been reported to alter horizontal-cell coupling in cone-driven horizontal cells, the junctional conductance between paired horizontal cells of skate was greatly reduced by the application of 20 mM acetate, which is known to effectively reduce intracellular pH. Together with the results obtained in situ on the receptive-field properties of skate horizontal cells, these findings indicate that the gap-junctional properties of rod-driven horizontal cells of the skate are fundamentally different from those of cone-driven horizontal cells in other species. This raises the possibility that there is more than one class of electrical synapse on vertebrate horizontal cells.
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PMID:Gap-junctional properties of electrically coupled skate horizontal cells in culture. 848 91

1. Intracellular recordings were used to study the role of metabotropic glutamate receptors (mGluRs) in modulating GABA-mediated giant depolarizing potentials (GDPs) in immature rat hippocampal CA3 neurones. 2. The mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM) reduced the frequency of GDPs. The broad-spectrum ionotropic glutamate receptor antagonist kynurenic acid (1 mM) blocked GDPs. 3. In the presence of kynurenic acid, both tetanic stimulation of the hilus or bath application of quisqualic acid (1 microM) and trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 20 microM) induced the appearance of GDPs. These effects were antagonized by MCPG (1 mM) or L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and blocked by bicuculline (10 microM). 4. 8-Bromo-cAMP (8-Br-cAMP, 0.3 mM), 3-isobutyl-1-methylxanthine (IBMX, 200 microM) or forskolin (30 microM) mimicked the effects of mGluR agonists on GDPs. The forskolin analogue 1,9-dideoxyforskolin (30 microM), which does not activate adenylate cyclase, was ineffective. 5. Incubation of slices in the presence of the protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) (500 microM) or superfusion of Rp-cAMPS (20 microM) prevented the effects of forskolin or t-ACPD on GDPs. In the presence of kynurenic acid, the protein kinase C activator, phorbol 12,13-diacetate (2 microM) induced the appearance of GDPs. This effect was prevented by staurosporine (1 microM). However, staurosporine (1-3 microM) did not modify the effects of t-ACPD on GDPs. 6. It is suggested that, during development, mGluRs enhance the synchronous release of GABA, responsible for GDPs, through cAMP-dependent protein kinase.
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PMID:Cyclic AMP-dependent modulation of giant depolarizing potentials by metabotropic glutamate receptors in the rat hippocampus. 858 96

Group III metabotropic glutamate receptors (mGluR4, 6, 7, 8) are negatively coupled to adenylate cyclase and, when activated presynaptically, decrease the release of glutamate and GABA. We have used intracerebroventricular injections of agonists and antagonists believed to act selectively on these receptors to study the pro- or anti-convulsant effects of mGluR III activation in nonepileptic (Swiss-Webster) and epileptic (DBA/2) mice. In both mouse strains the prototypic agonists L-2-amino-4-phosphonobutanoate (LAP4) and L-serine-O-phosphate are proconvulsant. The supposed antagonists (S)-2-methyl-2-amino-4-phosphonobutanoate (MAP4) and (RS)-alpha-methyl-4-phosphonophenylglycine (MPPG), have a predominantly proconvulsant effect. (S)-alpha-methyl-3-carboxyphenylalanine, which is a potent and selective antagonist for LAP4 in the cortex, is anticonvulsant in DBA/2 mice and decreases the convulsant effect of N-methyl-D-aspartate, 3,5-dihydroxyphenylglycine, LAP4 and MPPG in Swiss-Webster mice. These data suggest that reduced inhibitory transmission may be more significant than reduced synaptic release of glutamate following group III mGluR activation.
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PMID:Convulsant and anticonvulsant actions of agonists and antagonists of group III mGluRs. 885

Norepinephrine and the beta-adrenergic receptor agonist, isoproterenol, have been shown to potentiate the amplitude of GABAA receptor-mediated whole-cell current responses in Purkinje cells acutely dissociated from the rat cerebellum. However, the steps leading from the activation of beta-adrenergic receptors to the modulation of GABAA receptor remain to be delineated. This study tested the hypothesis that a sequelae of intracellular intermediaries involving the cyclic AMP second messenger system serves as the subcellular link to promote this heteroreceptor interaction. Exposure to cholera toxin, but not to pertussis toxin, increased the amplitude of GABA-activated current responses in acutely dissociated Purkinje cells. Intracellular dialysis with guanosine 5'-O-(3-thiotriphosphate) also resulted in a time- and dose-dependent augmentation of the response to GABA. while guanosine 5'-O-(2-thiodiphosphate) blocked the norepinephrine-mediated facilitation. A positive modulation of the current response to GABA was observed following intracellular delivery of cyclic AMP or the catalytic subunit of the cyclic AMP-dependent protein kinase. Furthermore, the norepinephrine-induced potentiation of the GABA-activated current response was prevented in the presence of the Rp isomer of cyclic AMP, the regulatory subunit of cyclic AMP-dependent protein kinase and an inhibitor of cyclic AMP-dependent protein kinase. These findings led to the formulation of a working model in which activation of the beta-adrenergic receptor triggers a Gs-protein-mediated transduction cascade in cerebellar Purkinje cells which activates adenylate cyclase, resulting in a rise in intracellular levels of cyclic AMP, increased phosphorylating activity by cyclic AMP-dependent protein kinase and, ultimately, a potentiation of GABAA receptor function.
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PMID:Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cyclic AMP as intracellular intermediary. 888 79

1. Protein kinase modulation of gamma-aminobutyric acid-A (GABAA)- and glycine-activated Cl- currents in freshly dissociated, morphologically identified rabbit retinal rod bipolar cells was studied under voltage clamp with the use of the whole cell patch-clamp technique. Responses to pulses of GABA and glycine were monitored before, during, and after application of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) and protein kinase C (PKC) activators, inactive analogues, and inhibitors. 2. Bath perfusion with either forskolin, an adenylate cyclase activator, or its inactive analogue, 1,9 dideoxyforskolin, reduced the GABA-activated Cl- currents by 30-50%; coapplication of N-[2-(Methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8), a PKA inhibitor, did not prevent the forskolin effects. The membrane-permeable cAMP analogues, 8-bromo-cAMP and 8-(4-Chlorophenylthio)-cAMP, and intracellularly dialyzed cAMP, did not modulate either the GABA- or glycine-activated Cl- current. Perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) had no direct effect on the GABA-activated current and did not alter the results with cAMP or its membrane-permeable analogues. Collectively, these results make it very unlikely that PKA represents an important mechanism of either GABAA or glycine channel modulation in the rabbit rod bipolar cell. 3. Although the isoquinoline sulfonamide protein kinase inhibitor H-8 was without discernible effect, the related compounds 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochlorine (H-7) and N-(2-Aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9) both dramatically reduced the GABA response. H-7 also strongly reduced the response to glycine, whereas H-8 had no effect and H-9 had an intermediate effect. Because only certain members of this inhibitor class of agents proved effective, and their effectiveness appeared unrelated to the established activity profiles, these agents probably inhibit the Cl- currents in a phosphorylation-independent manner. Direct interaction of these inhibitors with binding sites in the GABAA receptor-channel complex has been previously reported in some other preparations. 4. The phorbol ester and PKC activator phorbol 12,13 dibutyrate (PDB) led to a 35-55% reduction in the GABA-activated Cl- current of the rod bipolar cell. The broad-spectrum kinase inhibitor staurosporine, and the more PKC-specific inhibitor calphostin C, had no direct effect on GABA responses, but prevented Cl- current reduction when coapplied with PDB. Phorbol 12-myristate 13-acetate (PMA) reduced the GABA-activated current in a fashion very similar to PDB. Staurosporine and calphostin C blocked the PMA effect. No reduction of Cl- current was seen with the inactive analogue, 4-alpha-PMA, used as a control for PKC-independent phorbol ester effects. 5. PDB effectively reduced the GABA-activated Cl- current of the rod bipolar cell at low concentrations, whereas PMA had a diminished effect at low concentrations. This is consistent with the reported concentration-dependent abilities of these agents to promote translocation of PKC-alpha immunoreactivity from the membrane to the cytosolic compartment in the rabbit retinal rod bipolar cell. Collectively, the data from phorbol esters, inactive analogues, and kinase inhibitors support the existence of a PKC-mediated mechanism for GABA-activated Cl- current reduction in these cells. 6. The naphthalenesulfonamide PKC activator N-(n-Heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) also potently and reversibly reduced the GABA-activated current. Staurosporine and calphostin C eliminated this effect. When the nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue guanosine 5'-O-(3-thiotriphosphate) tetralithium salt (GTP-gamma-S) replaced GTP in the recording pipette, the SC-10-mediated GABA current reduction became irreversible.(ABSTRACT TRUNCATED)
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PMID:Protein kinase modulation of GABAA currents in rabbit retinal rod bipolar cells. 893 Feb 56

The effects of chronic morphine administration (dependence) and naloxone-induced withdrawal on cerebral GABAB receptor and its signal transduction system were examined. Alterations in receptor affinity and number and in the amount of Gi protein were determined by radioligand binding assay and immunoblotting with Gi protein antibody, respectively. [3H]GABA binding to GABAB receptors in the brain of morphine-dependent and -withdrawn mice showed no significant change in either high or low affinity sites. Similarly, no alterations were noted in the coupling between GABAB receptor and Gi protein or in the amount of protein. However, the suppressive effect of baclofen, a GABAB agonist, on forskolin-stimulated cAMP formation in cerebral cortical slices of these animals was abolished. These results indicate that chronic morphine administration may induce functional deterioration in the coupling between Gi protein and the adenylate cyclase system.
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PMID:Disappearance of gamma-aminobutyric acid (GABA)B receptor-mediated cAMP suppression in mouse cerebrum after chronic treatment with morphine. 895 Mar 21

1. We studied the ontogenetic development of GABAB receptors and their coupling to cyclic AMP formation in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rat brains. GABAB receptor binding to various brain regions was compared in age-matched SHR and WKY rats. 2. The specific [3H]-GABA binding to the posterior hypothalamus (PH) was significantly lower in not only 4 week old (normotensive) but also 11 week old (hypertensive) SHR, when compared with age-matched WKY. 3. Moreover, GABAB receptor agonists (baclofen and DN-2327)-induced suppression of adenylate cyclase activity also showed a decrease in 4 week old and 11 week old SHR PH. 4. We concluded that the number and the functional responsiveness of GABAB receptors in rat brains decrease in SHR, preceding blood pressure elevation. The activity of GABABergic mechanisms may be different in the brains of SHR and WKY rats.
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PMID:Functional alteration of the GABAB receptor in the brain of spontaneously hypertensive rats. 907 41


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