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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of GRF secretion was studied using a fetal rat hypothalamic cell culture system. The cells were subjected to short term release experiments on days 10-18 after plating, and GRF secretion was assessed by RIA. The identity of GRF immunoreactivity in the incubation medium was confirmed by reverse phase liquid chromatographic analysis. Depolarization of the cells with 56 mM K+ evoked a 4-fold increase in basal GRF release. When cultures were pretreated for 6 days with the adenylate cyclase activator forskolin, basal GRF release was augmented in subsequent release experiments to levels 2-fold greater than those in the control cultures. In nonpretreated cultures, forskolin (1-100 microM) and the protein kinase C activator phorbol 12-myristate 13-acetate (10 nM-1 microM), stimulated basal GRF release in a dose-dependent fashion. The Ca2+ channel blocker verapamil (100 microM) significantly inhibited the GRF response to both forskolin and phorbol 12-myristate 13-acetate. The gamma-aminobutyric acid (GABA) agonist muscimol (0.1-10 microM) inhibited forskolin-stimulated, but not K+ stimulated, GRF release in a dose-dependent manner. This inhibition was reversed by the GABA antagonists bicuculline and picrotoxinin. Muscimol (10 microM) slightly suppressed basal GRF release. The present findings suggest that GRF secretion can be evoked by agents known to increase intracellular cAMP levels or activate protein kinase-C. They also support a role for GABA in the inhibitory control of GRF secretion.
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PMID:Growth hormone-releasing factor secretion from fetal hypothalamic cell cultures is modulated by forskolin, phorbol esters, and muscimol. 253

Preparations of gamma-aminobutyrate (GABA)/benzodiazepine receptor from pig cerebral cortex are composed of three major bands of polypeptides (51, 55 and 57 kDa) which are purified in a ratio of approx. 2:1:1 respectively. Treatment of purified receptor preparations with cyclic AMP-dependent protein kinase resulted in major incorporation of 32P into the 55 kDa band only. The maximum incorporation achieved was 0.6 mol of 32P/mol of 55 kDa polypeptide. The phosphorylated receptor subunit (beta-subunit) displays the same apparent Mr as a band labelled irreversibly with the GABA receptor agonist [3H]muscimol. The two nonphosphorylated subunit polypeptides (51 and 57 kDa) are each labelled irreversibly with [3H]flunitrazepam and are recognized by anti-peptide antibodies specific for alpha-subunits.
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PMID:Phosphorylation of gamma-aminobutyrate (GABA)/benzodiazepine receptors by cyclic AMP-dependent protein kinase. 254 95

Immunohistochemical techniques and antibodies to gamma-aminobutyric acid (GABA), parvalbumin, and cyclic guanosine monophosphate-dependent protein kinase were used to identify populations of cerebellar neurons in culture that exhibit morphological features and immunoreactivity characteristic of neuronal types present in the cortical region of the cerebellum in vivo. The cultures were examined at 3 culture ages: 6-9, 12-15 and greater than 15 days in vitro, reflecting early, intermediate and late periods in cerebellar development. Neurons identified as Purkinje neurons (PNs), granule cells or inhibitory interneurons (stellate, basket, Golgi and Lugaro cells) were present at all culture ages. The granule cells (GCs) and inhibitory interneurons (INs) were morphologically well developed at the youngest culture age studied; morphological features did not change dramatically during the culture period. In contrast, the PNs were morphologically immature at 6-9 DIV (DIV = days in vitro) and exhibited dramatic changes in morphological structure with culture age. Extracellular recordings from PNs. GCs and INs in living cultures revealed that all classes of neurons exhibited spontaneous activity, but that only a portion of the GCs and INs were spontaneously active. The spontaneously active GCs and INs exhibited variable patterns of activity and low firing rates (approximately 2-6 Hz) at all culture ages studied. At 6 DIV, PNs exhibited firing rates and patterns similar to that of the interneurons. At older culture ages, the firing rate and pattern of PNs was significantly different from the GCs and INs and was characterized by high frequency (greater than 10 Hz) spike activity usually in a regular pattern. All cerebellar neurons by excited by the transmitter glutamate (Glu). The Glu response in the GCs and INs consisted of a brief burst of single spikes; in PNs, the response to Glu was prolonged and multiphasic. These data indicate that the cerebellar GCs and INs express morphological, physiological and developmental properties that are significantly different from the PN.
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PMID:Morphological and physiological properties of rat cerebellar neurons in mature and developing cultures. 290 61

The synapse is a major regulatory site that has been implicated in modulating neuronal excitability and seizure discharge. Voltage-dependent calcium (Ca2+) entry at the synapse plays a major role in initiating neurotransmitter release and in regulating synaptic function. Thus, obtaining a molecular understanding of the effects of Ca2+ on synaptic modulation would provide important insights into the regulation of synaptic activity and, possibly, the biochemical basis for some forms of epilepsy. Calmodulin is a major Ca2+-binding protein in brain that has been implicated in mediating many of the second messenger effects of Ca2+ on neuronal function. The evidence implicating calmodulin in modulating synaptic excitability will be presented. Calmodulin was shown to be present at the synapse in association with synaptic vesicles and in the postsynaptic density. In addition, several calmodulin-regulated synaptic biochemical processes have been identified, including Ca2+- and calmodulin-regulated protein phosphorylation, vesicular neurotransmitter release, vesicle-membrane interactions, and neurotransmitter turnover. These results indicate that calmodulin may play an important role in synaptic modulation and provide a molecular approach to investigating the Ca2+ signal in brain. Several anticonvulsants have been shown to regulate some of calcium's effects on neuronal function. These anticonvulsants include phenytoin, carbamazepine, and the benzodiazepines. All of these compounds are effective against maximal electric shock (MES) seizure models in animals. Anticonvulsants were tested on several of the Ca2+-calmodulin-regulated synaptic biochemical systems. The results demonstrate that phenytoin, carbamazepine, and the benzodiazepines were effective in inhibiting calcium calmodulin protein kinase activity in membrane and purified kinase preparations, vesicle neurotransmitter release, vesicle-membrane interactions, and voltage-sensitive calcium uptake in intact synaptosomes. Phenobarbital, ethosuximide, trimethadione, valproic acid, and vinyl gamma-aminobutyric acid (GABA) were not effective in inhibiting these calcium-regulated processes. Thus, the effects of anticonvulsants on calcium-regulated processes were selective to a group of anticonvulsants that had been shown in several electrophysiological systems to antagonize some of the actions of calcium on neuronal excitability. These observations suggested the existence of specific membrane receptors that might mediate the effects of these anticonvulsants on neuronal function through the regulation of calcium-calmodulin-regulated processes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A molecular approach to the calcium signal in brain: relationship to synaptic modulation and seizure discharge. 301 Jun 80

The hypothesis that protein kinase C (PKC) plays a role in the release of dopamine (DA) in the nigrostriatal pathway was examined. It was found that injections of apomorphine, SKF 38393 (D1 agonist), LY 171555 (D2 agonist) or gamma-butyrolactone (GBL) (which decreases impulse-induced release of DA) resulted in a decrease in particulate, and an increase in soluble, PKC activity. Injections of fluphenazine, haloperidol, SCH 23390 (D1 antagonist), sulpiride (D2 antagonist) or picrotoxin (gamma-aminobutyric acid antagonist which increases DA release transneuronally) had the opposite effect of increasing particulate and decreasing soluble PKC activity. The total activity was not changed. These effects were receptor mediated since the effect of each agonist could be reversed by its specific antagonist. These drugs influenced PKC in the striatum in a dose-dependent manner. In contrast, no effects were seen in the cerebellum, a region with sparse dopaminergic innervations. The change in PKC activity was mediated via a change in the Km for calcium, while the Vmax was unchanged. The phosphorylation of endogenous substrate proteins by PKC was also altered by injections of these drugs. Besides affecting PKC, these DA acting drugs also affected the calmodulin-dependent protein kinase activity, but the direction of change was opposite to that for PKC. In a synaptosomal preparation, PKC acting drugs also affected the depolarization-induced release of DA. Adriamycin and melittin decreased the potassium-induced release of DA, whereas tetradecanoyl-phorbol-13-acetate (TPA) enhanced this release. These results showed that there was a good correlation between the ability of drugs to alter the impulse-induced release of DA in vivo and their ability to affect changes in particulate and soluble PKC activity. They lend support to the hypothesis that PKC, together with calmodulin, plays a key role in the release of DA in the nigrostriatal pathway.
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PMID:Protein kinase C and dopamine release--II. Effect of dopamine acting drugs in vivo. 305 15

Dopamine (DA)-containing neurons of the rat retina are apparently activated transsynaptically by photic stimulation. Exposure of dark-adapted rats to light increases retinal DA biosynthesis and metabolism. Associated with the light-evoked increase of DA biosynthesis is a rapid activation of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis. The activation of TH is characterized by an increased affinity of the enzyme for the pteridine cofactor. Because TH in dark-adapted retinas is apparently not saturated with cofactor, the light-evoked increase of affinity is probably responsible for the observed stimulation of DA biosynthesis. Cyclic AMP (cAMP)-dependent protein phosphorylation in vitro activates TH extracted from dark-adapted retinas, and phosphorylation-induced TH activation is very similar and not additive with light-evoked activation of the enzyme. Incubation of viable cell suspensions of dissociated retinas with 8-bromo cAMP also activates TH, which indicates the availability of sufficient cAMP-dependent protein kinase in the proper subcellular compartment to regulate the enzyme in situ. The DA-containing neurons of the rat retina are tonically inhibited in darkness, and evidence is presented that this tonic inhibition involves direct synaptic input to the DA neurons from gamma-aminobutyric acid-containing amacrine cells. The DA-containing neurons are also subject to feedback inhibition through DA receptors, and to modulation by alpha 2-adrenergic receptors.
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PMID:Regulation of retinal dopamine biosynthesis and tyrosine hydroxylase activity by light. 614 73

Extraneurally released gamma-aminobutyric acid (GABA) interacts with specific recognition sites associated with proteins located in postsynaptic neuronal membranes that function as chloride (Cl-)ionophores. As a result of the interaction between GABA and the recognition sites, Cl- ionophores are opened causing an influx or an efflux of Cl-, depending on the values of the Cl- equilibrium potential and of the membrane potential. Hyperpolarization or depolarization will result from inward or outward Cl- fluxes, respectively. Independently of the change in conductivity elicited by GABA, this amino acid transmitter will reduce the effectiveness of the sodium ion (Na+) excitatory potential. In attempts to elucidate the molecular mechanism, whereby benzodiazepines facilitate the action of GABA on membrane conductance without changing the activity of Cl- or other ionophore, a basic protein (GABA-modulin, GM) has been isolated from rat brain which is similar in structure to the small molecular weight myelin basic protein, found in rodent brain. While GABA-modulin is located in synaptosomes, the small molecular weight myelin basic protein is located in the myelin fraction: more important, GABA-modulin inhibited the high affinity binding of GABA to crude synaptic membranes while the basic myelin protein did not. Also, amino acid composition and molecular weight differentiate the two proteins. The GABA-modulin can be phosphorylated with different stoichiometry by cyclic AMP-dependent protein kinase (4 mol PO4(-3)) or Ca2+-dependent protein kinase (1 mol PO4(-3)). Only cyclic AMP-dependent phosphorylation inhibited the action of GABA-modulin on GABA binding.
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PMID:GABAergic synapses. Supramolecular organization and biochemical regulation. 632 41

1. The tight-seal whole cell recording technique was used to study the effects of the metabotropic glutamate receptor (mGluR) agonist, trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) on spontaneous gamma-aminobutyric acid (GABA)-mediated synaptic currents in neonatal rat CA1 hippocampal neurons in slices obtained from postnatal (P) days P6-P12. 2. Bath application of t-ACPD (3-30 microM), in the presence of kynurenic acid, induced a concentration-dependent increase in frequency but not in amplitude of spontaneous GABAergic currents. The mean frequency ratio (t-ACPD 10 microM over control) was 2.6 +/- 1 (mean +/- SD), whereas the mean amplitude ratio was 1.1 +/- 0.3. 3. The effect of t-ACPD was partially antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM). 4. t-ACPD (10-30 microM) did not modify the frequency of miniature GABAergic synaptic currents recorded in tetrodotoxin (the mean frequency ratio of t-ACPD over control was 0.7 +/- 0.3). 5. Forskolin (30 microM), but not its analogue 1,9 dideoxyforskolin (30 microM), mimicked the effect of t-ACPD. Similar effects were obtained with 3-isobutyl-1-methylxanthine (IBMX, 200 microM). 6. The potentiating effect of t-ACPD on spontaneous GABAergic currents was prevented by Rp-cAMPS (30 microM), a specific antagonist of protein kinase A. This suggests that mGluRs localized at the soma-dendritic level of GABAergic interneurons and positively coupled to cyclic AMP may modulate GABA release during a critical period of postnatal development.
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PMID:Activation of metabotropic glutamate receptors increase the frequency of spontaneous GABAergic currents through protein kinase A in neonatal rat hippocampal neurons. 750 Jan 37

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate nervous system. Modulatory effects of intracellular ATP on the GABA response in isolated bullfrog dorsal root ganglion neurons were examined using whole-cell voltage clamp. Investigation of the plausible mechanisms ATP might utilize to regulate the GABA response led to the discovery that intracellular cyclic GMP may play an important role in modulating inhibitory neurotransmission. This modulatory effect of cyclic GMP is likely to be mediated via a cyclic GMP-dependent protein kinase.
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PMID:gamma-Aminobutyric acidA receptor function is modulated by cyclic GMP. 760 81

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.
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PMID:Drosophila gamma-aminobutyric acid receptor gene Rdl shows extensive alternative splicing. 768 73


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