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)

Striatal neurons were cultured from fetal mouse brain and maintained in serum-free medium for 14-21 days in vitro (DIV). A double coating of culture dishes with polyornithine and fetal calf serum was needed in order to obtain synaptic differentiation. Synaptic vesicles were present in axon terminals as well as in varicosities along extended axons. The presence of differentiated synapses was confirmed by the immunostaining of the preparation with synapsin I antibody. After 13 days in vitro synapsin I was present in axonal varicosities and particularly concentrated at contact points between axonal terminals and postsynaptic sites on adjacent axons or perikarya. On a surface of 429 mm2 on which 2211 cells were observed under phase contrast microscopy only 7% were stained with an antibody against GFAP (glial fibrillary acidic protein). One or two days after the formation of differentiated synapses (11 DIV), a Ca2+-dependent liberation of GABA was observed. These cultures are an excellent model for studying the coupling of some neurotransmitter receptors with an adenylate cyclase. In particular using this preparation we were able to demonstrate that dopamine (D2) and serotonin-(5-HT1) receptors are negatively coupled with an adenylate cyclase. These cultures are also an excellent model to study the coupling of some neurotransmitter receptors with inositol phosphate producing enzymes. We demonstrated for the first time that the quisqualate subtype of glutamate receptors is able to increase inositol phosphate production in striatal neurons.
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PMID:Primary culture of striatal neurons: a model of choice for pharmacological and biochemical studies of neurotransmitter receptors. 288 8

In this communication, I have summarized our studies on the possible roles of cysteine sulfinic acid (CSA) in the central nervous system (CNS), from these observations, CSA was suggested to be a neurotransmitter. We reported the presence of CSA in the CNS and subsequently characterized Na+-dependent high affinity uptake and depolarization-induced release of CSA. Depolarization-induced release of [14C]CSA from the preloaded hippocampal slices was specifically attenuated by benzodiazepines and GABA agonists. Synaptic membranes have a Na+-dependent specific binding site for cysteic acid, an analogue of CSA, which may be a possible binding site for CSA. This binding site seemed to be distinct from that for glutamate. To assess CSA as a physiologically active candidate which is distinct from glutamate, two neurochemical experiments were performed: one experiment determined the enhancement by excitatory amino acids of depolarization-induced release of [3H]GABA from the preloaded slices, and the other one monitored the cyclic AMP formation by excitatory amino acids in hippocampal slices. In both studies, differences in the responses to the various antagonists indicate that CSA receptors are distinct from glutamate receptors. Furthermore, we proposed that excitatory amino acid receptors which are subsequently linked to adenylate cyclase are functionally related to the Cl- channel.
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PMID:Neurochemical characterization of cysteine sulfinic acid, an excitatory amino acid, in hippocampus. 288 31

Noradrenaline and dopamine (0.1-100 microM) inhibited 45Ca2+ uptake and glutamate release induced by veratrine (25 microM) in cortical and striatal slices but were without effect when added alone. Each parameter was inhibited in a dose-dependent manner by noradrenaline in cortical slices (IC50 = 0.05 microM) and by dopamine in striatal slices (IC50 = 0.08 microM). Noradrenaline (0.01-100 microM) was without influence on veratrine-induced 45Ca2+ influx or glutamate release in the striatal preparation, and likewise dopamine was inactive in cortex slices. The use of adrenoceptor antagonists suggests that the action of noradrenaline is mediated by the alpha 2-receptor which is thought to be adenylate cyclase linked. Dopamine appeared to be acting through the D-2 receptor.
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PMID:Inhibitory effects of noradrenaline and dopamine on calcium influx and neurotransmitter glutamate release in mammalian brain slices. 289 52

1. Multiple-barreled microelectrodes were used to record from neurons in the area postrema of anesthetized dogs and to test the responses of the neurons to a variety of substances in this structure, which is known to function as the chemoceptive trigger zone for emesis. 2. The neurons in area postrema were silent at rest but could be "found" by virtue of their response to ionophoretic glutamate. The glutamic response was brief and of short latency with high frequency of discharge. 3. Dog area postrema neurons were also excited by over 20 other substances, including acetylcholine, the biogenic amines, several peptides, and at least two hormones. Not all agents were excitatory, however. 4. The responses to all excitatory agents except glutamate were similar and unusual. All responses showed a relatively long latency (3-20 s), a long duration of excitation (30 s to many minutes), and a low discharge frequency (1-3 Hz). 5. There was a good correlation between substances that were excitatory on area postrema neurons and substances known to cause emesis. Because emesis due to intravenous application of these substances is known to be abolished in animals with ablation of the area postrema, it is very likely that recordings were from the neurons which trigger the response. 6. Because so many substances elicit the same type of response there is a possibility that all utilize a common second messenger. Neurons were not excited by ionophoresis of guanosine 3',5'-cyclic monophosphate (cGMP) but were excited by 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) and by forskolin, an activator of adenylate cyclase. 7. Behavioral studies were performed looking for emetic responses in awake dogs following intravenous injection of apomorphine, insulin, angiotensin II, and leucine enkephalin. For each a threshold concentration could be determined, which would consistently evoke emesis. 8. Dogs pretreated with phosphodiesterase inhibitors (theophylline, 3-isobutyl-1-methylxanthine, or RO 1724) showed a shift in the threshold concentration of the above substances that triggered emesis, such that emesis was evoked by lower concentrations than in the control. 9. These results suggest that neurons of the dog area postrema trigger the emetic reflex in response to specific receptors for a great variety of transmitters, peptides, and hormones, and that these receptors act through a common second messenger, cAMP.
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PMID:Excitation of area postrema neurons by transmitters, peptides, and cyclic nucleotides. 289 67

The effect of forskolin on the excitatory amino acid-induced accumulation of cyclic AMP was examined in hippocampal preparations of the guinea pig. Forskolin at concentrations of 0.1-10 microM remarkably enhanced the stimulatory effects of histamine and adenosine, whereas it markedly attenuated the stimulation induced by cysteine sulfinate, an excitatory amino acid. Forskolin reduced the maximal response to cysteine sulfinate without affecting the apparent ED50. At a concentration of 1 microM, forskolin also inhibited the stimulatory effects of glutamate, N-methyl-DL-aspartate, and veratridine without affecting those of kainate and quisqualate. Pretreatment of the slices with 0.1 mM N-ethylmaleimide partially prevented the attenuation by forskolin of cysteine sulfinate-induced accumulation of cyclic AMP without affecting the stimulation induced by cysteine sulfinate. Forskolin at concentrations of less than 1 microM did not affect GTP-stimulated activity and Cl- -dependent activity of adenylate cyclase of the hippocampal membranes.
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PMID:Inhibition by forskolin of excitatory amino acid-induced accumulation of cyclic AMP in guinea pig hippocampal slices. 289 4

1. The utilization and control of glycogen stores were studied in the isolated segmental ganglia of the horse leech, Haemopis sanguisuga. The glycogen in the ganglia was extracted and assayed fluorimetrically and its cellular localization and turnover studied by autoradiography in conjunction with [3H] glucose. 2. The glycogen levels were measured after incubation with different neurotransmitters for 60 min at 28 degrees C. The results for each experimental ganglion were compared to a paired control ganglion, and the results analysed by paired t-tests. 3. Several transmitter substances (5-HT, octopamine, dopamine, noradrenaline, histamine) produced reductions in glycogen (glycogenolysis); other transmitters (glutamate, GABA) produced increases in glycogen (gluconeogenesis); others (adenosine, glycine) produced reductions or increases, depending on concentration. Acetylcholine had no effect on the glycogen levels. 4. Most of the glycogen in the ganglia is localized in the packet glial cells, which surround the neuron perikarya. Autoradiographic analysis demonstrated that the effects of histamine and dopamine were principally on the glycogen in the glial cells. 5. Adenylate cyclase was demonstrated by electron microscope histochemistry to be localized on the plasma membranes of the glial cells, and to a lesser extent on the neuronal membranes. 6. It is concluded that the changes in glycogen in the glial cells may be party controlled by transmitters via adenylate cyclase. This may provide a sensitive mechanism for coupling neuronal activity with energy metabolism.
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PMID:Transmitter-induced glycogenolysis and gluconeogenesis in leech segmental ganglia. 290 39

The actions and interactions of the neurotransmitter glutamate and the intracellular messengers calcium, cyclic AMP, and protein kinase C (PKC) in the regulation of neurite outgrowth and cell survival were examined in hippocampal pyramidal-like neurons in isolated cell culture. Low, subtoxic levels of glutamate (10-100 microM) caused the regression of dendrites but not axons; millimolar levels caused cell death. Calcium ionophore A23187 (50-100 nM) and the PKC activator phorbol-12-myristate-13-acetate (PMA; 10-50 nM) caused the regression of both axons and dendrites, whereas the adenylate cyclase activator forskolin enhanced outgrowth rates in both axons and dendrites. The effects of glutamate, A23187, PMA, and forskolin on outgrowth were mediated locally at the growth cones; dendrites were more sensitive than axons to each of these agents. High levels of A23187 (1 microM) or PMA (100 nM) significantly reduced cell survival. Co2+ and trifluoperazine each significantly reduced glutamate-induced dendritic regression and neurotoxicity suggesting that calcium influx and/or PKC activation mediated glutamate's actions. Fura-2 measurements showed that glutamate caused a rapid rise in intracellular calcium levels; this rise was prevented by Co2+. PMA and forskolin did not alter intracellular calcium levels, nor did these agents affect glutamate-induced calcium rises. Taken together, the results indicate that parallel intracellular messenger pathways that influence neurite outgrowth and cell survival are operative in hippocampal neurons; these messengers may play roles in the formation and modification of neuronal circuitry.
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PMID:Intracellular messengers in the generation and degeneration of hippocampal neuroarchitecture. 290 49

Electron cytochemical studies have been made of the effect of various concentrations of the glutamic acid on localisation of adenylate and guanylate cyclases in synaptosomes from the brain cortex of rats. It was found that the glutamic acid (10(-3) M) stimulates the activity of intrasynaptosomal adenylate cyclase, but does not affect postsynaptic pool of the enzyme. The effect of glutamate on guanylate cyclase results in the increase of the frequency of the reaction both in synaptosomal and postsynaptic membranes. It is suggested that in the conduction of glutamate signal, guanylate cyclase--cGMP, but not adenylate cyclase--cAMP, system may be involved, although activation of intrasynaptosomal adenylate cyclase indicates its participation in presynaptic processes.
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PMID:[Selective sensitivity of synaptosomal cyclases to glutamic acid]. 290 5

Glucagon has been shown to increase further the enhanced tolerance for hypoxia of mice with elevated blood ketones and to stimulate ketone utilization by rat brain slices, suggesting that glucagon may affect brain metabolism. In addition to stimulating gluconeogenesis, glucagon alters the metabolism of mitochondria isolated from liver and heart. This study was designed to test whether glucagon can act directly and selectively on brain mitochondrial substrate oxidation. Mitochondria were isolated from normal murine brains using differential centrifugation through Ficoll gradients. Glucagon (3.6 microM) stimulated respiration in the presence of glutamate, and glutamate plus beta-hydroxybutyrate, but not in the presence of glutamate plus malate, succinate or beta-hydroxybutyrate alone. With glutamate as the substrate the hormone significantly increased State 3 oxygen consumption rates from control values of 91 mol O2/mol of cytochrome aa3/min to 117 mols O2/mol/aa2/min (p less than 0.0001), and also increased State 4 rates slightly but significantly. Glucagon did not change mitochondrial respiratory control ratios, but increased estimated rates of ATP synthesis from 434 (control) to 597 mols ADP consumed/mol aa3/min (p less than 0.0001). The data indicate that in vitro glucagon has a direct and substrate-specific stimulatory effect on isolated brain mitochondria. These substrate-specific effects were not altered when respiration was studied in the presence of postmitochondrial supernatant or exogenous 3',5'-cyclic AMP, indicating that glucagon, in addition to an in vivo action via activation of membrane-bound adenylate cyclase, can act, at least in vitro, directly and selectively on brain mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Substrate-specific stimulation by glucagon of isolated murine brain mitochondrial oxidative phosphorylation. 300 83

Pertussis is a unique disease in which the harmful effects are mediated by an exotoxin that effects stimulation of the adrenergic system which is neuronally controlled. The interdependence of the growth of bacteria and toxin production, and the local colonization of the bacteria that precedes the clinical symptom of the disease reflect the nature of the disease. Pertussis toxin enzymatically alters the function of numerous regulatory cells that is demonstrable, after an interval of time, by a specific stimulus. The toxin also may act rapidly and effect action at a target tissue. The latter appears to be associated with the rapid adverse events after vaccination whereas both may occur in the disease. The pathophysiologic responses associated with specific clinical symptoms have not been clearly defined. Responses to be evaluated relative to encephalopathy are increased vascular permeability, hypoglycemia and enhanced activity of neuronal glutamate and aspartate. The intensity of responses is related to the amount of pertussis toxin available, genetic susceptibility, ethnic and allotype, and external factors. The reason for the non-linear dose response shown by the critical level between the sublethal and the lethal infection in mice is unclear. Bacterial adenylate cyclase may be a candidate. Much remains to be elucidated about the enzymatic pathways that effect the many disparate events, the identity of the neurons that effect the clinical symptoms and their CNS location, the identity of the neuronal transmitters and the pathoneuronal pharmacodynamics.
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PMID:Neurotoxicity of Bordetella pertussis. 302 80


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