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 cellular mechanisms underlying beta-adrenergic potentiation in the CA1 region of the rat hippocampus were examined. A 10 min treatment with isoproterenol (ISO) induced a long-term depolarization of the pyramidal neurons that persisted for at least 30 min of washout; the ISO-induced decrease in the calcium-activated potassium conductance (afterhyperpolarization, or AHP) was similarly prolonged. The long-term excitability changes induced by ISO did not depend upon the calcium concentration of the medium and could be elicited in medium containing as little as 240 microM calcium. The persistent increase in population spike induced by ISO was mimicked by superfusion with several cAMP analogs and by forskolin (which directly activates adenylate cyclase), but not by the inactive dideoxyforskolin. Forskolin and cAMP analogs also induced decreases in AHPs that could be quite prolonged, but did not depolarize pyramidal neurons as consistently as did ISO. We hypothesize that activation of beta-adrenergic receptors in the CA1 region of hippocampus may induce an alteration of the hippocampal "state" that can persist for as long as several hours, during which the induction of other forms of plasticity may be enhanced.
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PMID:Long-term increases in excitability in the CA1 region of rat hippocampus induced by beta-adrenergic stimulation: possible mediation by cAMP. 131 Oct 33

Autoradiographic localizations of major second messengers and a selective cyclic adenosine monophosphate (cyclic-AMP) phosphodiesterase in the brain were visualized in the gerbil and the rat using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]forskolin, [3H]cyclic-AMP, and [3H]rolipram were used to label protein kinase C, IP3 receptor, adenylate cyclase, cyclic-AMP-dependent protein kinase (cyclic-AMP-DPK), and Ca2+/calmodulin-independent cyclic-AMP phosphodiesterase (PDE), respectively. Most second messengers and rolipram binding activities were especially found in the limbic system, basal ganglia, and cerebellum. Marked differences were noted in the hippocampus, where cyclic-AMP and rolipram binding activities were very low in gerbils but high in rats. In contrast, regional localization in the binding sites of PDBu, IP3, and forskolin in gerbil brain was relatively similar to that in rat brain. Further, alteration of the cyclic-AMP and rolipram binding sites was studied in the gerbil hippocampus 7 days after 10-min cerebral ischemia. The results suggest that the gerbil differs from the rat with respect to the characteristic neurons or interneurons, especially in the hippocampal formation. This finding may help further elucidate the relationship or difference between gerbils and rats for brain function and behavioral pharmacology. Furthermore, our results suggest that cyclic-AMP and rolipram binding sites are predominantly distributed on the pyramidal cell layer of the hippocampal CA1 sector and that transient cerebral ischemia can cause marked reduction in these binding sites in the hippocampus.
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PMID:Mapping of second messenger and rolipram receptors in mammalian brain. 132 28

Vasoactive intestinal polypeptide added at submicromolar concentrations to the perfusion fluid of rat hippocampal slices and slice cultures enhanced the excitability of CA1 and CA3 pyramidal cells in several ways. Specifically, cells were depolarized and the Ca(2+)- and cyclic AMP-dependent potassium conductance was blocked as demonstrated by reduction of the long-lasting afterhyperpolarization and the accommodation of firing. This was also found in tetrodotoxin-containing medium. In low Ca(2+)-high Mg2+ medium (in synaptic isolation) the firing rate was increased. Synaptic transmission was potentiated: extracellularly registered excitatory postsynaptic potentials and population spikes in response to stratum radiatum stimulation and intracellularly recorded excitatory postsynaptic potential-inhibitory postsynaptic potential sequences were enhanced. These results are in keeping with the known stimulation of adenylate cyclase by vasoactive intestinal polypeptide.
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PMID:Vasoactive intestinal polypeptide modulates neuronal excitability in hippocampal slices of the rat. 132 9

Using a strategy based on amino acid sequence homology between 5-hydroxytryptamine (5-HT) receptors that interact with G proteins, we have isolated from a mouse brain library a cDNA encoding a new serotonin receptor, the 5HT1E beta receptor. Amino acid sequence comparisons revealed that its closest relatives were the recently characterized 5HT1E receptor (S31) and the 5HT1B and 5HT1D receptors. When expressed transiently in Cos-7 cells, the 5HT1E beta receptor displayed a high affinity for the nonspecific serotonergic radioligand 2-[125I]iodolysergic acid diethylamide (Kd = 980 pM). The pharmacological profile of the 5HT1E beta receptor resembled that of previously reported 5HT1E sites that have a low affinity for 5-carboxamidotryptamine and that have been found in human and rat brain. When stably expressed in NIH-3T3 cells, the 5HT1E beta receptor was negatively coupled to adenylate cyclase. In situ hybridization experiments revealed that the 5HT1E beta transcripts were detected only in the CA1, CA2, and CA3 layers of the hippocampus. Our results therefore demonstrate that the 5HT1E receptors constitute a heterogeneous family of receptors.
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PMID:Isolation of a mouse "5HT1E-like" serotonin receptor expressed predominantly in hippocampus. 132 80

The Mongolian gerbil was used as a model of aging because of its relatively short lifespan, genetic homogeneity and the fact that data had been collected previously. Furthermore, gerbils have been widely used in biomedical investigations of stroke and epilepsy. Age-related differences in signal transmission and transduction systems were investigated in brains of three-, 11- and 21-month-old gerbils by morphological and in vitro receptor autoradiographic studies. Morphometric analysis revealed a decreased number of neurons in layer III of the occipital cortex and also a decrease in cerebellar Purkinje cells in 21-month-old animals. However, no statistical differences were observed in the hippocampal formation, the dorsolateral striatum and layer III of the frontal cortex. Autoradiography was used to map muscarinic cholinergic (labeled with [3H]quinuclidinyl benzilate), serotonin2 ([3H]spiperone), dopamine D2 ([3H]spiperone), adenosine A1 ([3H]cyclohexyladenosine), GABAA ([3H]muscimol), naloxone ([3H]naloxone), protein kinase C ([3H]phorbol 12,13-dibutyrate), adenylate cyclase ([3H]forskolin), cyclic AMP ([3H]cyclic AMP) and L-type Ca2+ channels ([3H]PN200-110). Muscarinic cholinergic receptor and protein kinase C, cyclic AMP and L-type Ca2+ channels were significantly decreased in the cerebral cortex and/or in the CA1 subfield of the hippocampus in the 21-month-old group. Muscarinic cholinergic receptor and L-type Ca2+ channel binding sites were significantly reduced in the dentate gyrus. In contrast, protein kinase C was increased in this area in the 21-month-old group. Also, naloxone binding sites were increased in the CA3 subfield, hilus, dentate gyrus and molecular layer of the cerebellum in the 11- and 21-month-old groups. Muscarinic cholinergic, serotonin2 and dopamine D2 receptors and adenylate cyclase were significantly decreased in the striatum. On the other hand, adenosine A1 and GABAA receptors remained unchanged in the 21-month-old group. Although age-related histopathological abnormalities were only observed in the occipital cortex and in the cerebellum, alterations of signal transmission and transduction systems were noticed in all areas examined (e.g. cerebral cortex, CA1 subfield, dentate gyrus and striatum). These data indicate that changes in these receptors and binding sites may be related to dysfunction of learning and memory and to the loss of motor function. The aged gerbil model is a good system for studying aging and is of value for simulating aging after epilepsy and stroke.
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PMID:Effects of aging on signal transmission and transduction systems in the gerbil brain: morphological and autoradiographic study. 134 8

Activation of cAMP-dependent protein kinase (kinase A) has recently been shown to enhance responses evoked by stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured hippocampal pyramidal neurons. Here we report results of experiments designed to determine if activation of the cAMP cascade potentiates synaptic strength in field CA1 of rat hippocampal slices. We find that bath application of the direct adenylate cyclase activator forskolin (50 microM) enhances the field excitatory postsynaptic potential (EPSP) slope and population spike amplitude evoked by stimulation of Schaffer/commissural afferents. This effect is potentiated by the phosphodiesterase inhibitor and adenosine receptor antagonist 3-isobutyl-1-methylxanthine (IBMX). The enhancement produced by forskolin is suppressed in the presence of adenylate cyclase inhibitors and is not mimicked by the inactive forskolin analogue 1,9-dideoxyforskolin, indicating that, indeed, activation of adenylate cyclase mediates the effects of forskolin in field CA1. Our observations support the idea that changes in intracellular cAMP levels can modulate synaptic efficacy of excitatory glutamatergic synapses in the mammalian hippocampus.
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PMID:Modulation of synaptic efficacy in field CA1 of the rat hippocampus by forskolin. 137 10

The alterations of second-messenger ligand binding and cerebral blood flow (CBF) were evaluated in the gerbil brain after 2-h unilateral common carotid artery occlusion. [3H]Forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu) were used as specific ligands for adenylate cyclase (AC) and protein kinase C (PKC) activity estimation, respectively. CBF was determined at the end of the experiment by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted simultaneous measurement of the three parameters in the same brain. The levels in the caudate-putamen, globus pallidus, and hippocampus were analyzed. The animals were divided into three groups: Group 1 with severe ischemia (CBF in the lateral nuclei of the thalamus (CBFt) less than 50 ml/100 g/min), Group 2 with mild ischemia (CBFt greater than or equal to 50 ml/100 g/min), and the Sham Group. The PDBu binding revealed a statistically significant increase in the caudate-putamen, lateral nuclei of the thalamus and hippocampus (CA1 and CA3 regions and dentate gyrus) on the ischemic side in Group 1 as compared to that in Group 2 and the Sham Group. In contrast, the FK binding did not show any significant changes in any of the regions. These data and our previous findings for 6-h ischemia suggest that (1) PKC translocation to the cell membrane may occur at the early ischemic phase in particular regions including the caudate-putamen, lateral nuclei of the thalamus and hippocampus, with the translocated PKC gradually diminishing during the subsequent ischemic period; and (2) the suppression of the AC system observed in 6-h ischemia may not appear in the early ischemic phase.
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PMID:Alteration of second-messenger ligand binding following 2-hr hemispheric ischemia in the gerbil brain. 139 61

To clarify the role of muscarinic acetylcholine receptors in the hypoxia/hypoglycemia (ischemia)-induced functional deficit in hippocampal neurons, we examined the effect of cholinergic drugs on ischemia-induced impairments of glucose uptake and CA1 field potentials in hippocampus slices. Muscarinic receptors were subdivided into M1 (high affinity for pirenzepine) and M2 (low affinity for pirenzepine) subtypes. The M1 receptor subtype is coupled to an increase in phosphoinositide hydrolysis and the M2 receptor subtype is associated with inhibition of adenylate cyclase. The greater potency of carbachol in stimulating phosphoinositide hydrolysis resulted in exacerbated ischemia-induced deficits. Treatment with the muscarinic receptor antagonists scopolamine and pirenzepine (M1 receptor-selective antagonist) had a strong dose-dependent protective effect against ischemia-induced deficits. Oxotremorine and McN-A-343, weak stimulators of phosphoinositide hydrolysis and strong inhibitors of adenylate cyclase, had a weak neuroprotective action against ischemia-induced deficits. These results suggest that stimulation of M1 muscarinic receptors coupled with an increase in phosphoinositide hydrolysis may play a facilitatory role in ischemia-induced deficits. Stimulation of M2 muscarinic receptors may play an inhibitory role in ischemia-induced neuronal deficits.
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PMID:Effect of muscarinic cholinergic drugs on ischemia-induced decreases in glucose uptake and CA1 field potentials in rat hippocampus slices. 145 86

The GTP binding protein, Gs, activates adenyl cyclase in direct response to stimulation of several neurotransmitter receptors. In situ hybridization histochemistry (ISHH) with a 35S-labelled oligonucleotide has been used to detect the mRNA encoding the alpha subunit of Gs (Gs alpha) in human hippocampus, temporal and visual cortices and cerebellum, and its level has been compared between Alzheimer's disease (AD) and control brains. A marked regional increase was found in the hippocampus of AD cases. Analysis of levels of Gs alpha mRNA in individual constituent pyramidal cells confirmed this increase (3 to 4-fold in densitometric units) in hippocampal fields CA1, CA3 and CA4, as well as in temporal cortex. Levels of Gs alpha mRNA were also determined relative to total poly(A)+ mRNA in the same cell populations in each case. Gene-specific elevation of Gs alpha mRNA was thereby confirmed in hippocampal fields, and also in temporal cortex. No changes were seen in visual cortex. The increase in Gs alpha mRNA may represent a response by AD neurons in affected areas to receptor alterations, or to an abnormality in receptor-G protein coupling. Alternatively, altered G protein gene expression might be a pathogenic event underlying changes in linked receptor populations.
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PMID:Alzheimer's disease: specific increases in a G protein subunit (Gs alpha) mRNA in hippocampal and cortical neurons. 164 85

Changes in second messenger and neurotransmitter system receptor ligand binding induced by transient forebrain ischemia were studied in the gerbil hippocampus. The animals were allowed variable periods of recovery ranging from 2 h to 7 days after 5-min bilateral carotid artery occlusion. The binding of second messenger systems ([3H]inositol 1,4,5-trisphosphate ([3H]IP3)to inositol 1,4,5-triphosphate, [3H]forskolin to adenylate cyclase and [3H]phorbol 12,13-dibutylate to protein kinase C) and neurotransmitter receptor systems ([3H]PN200-110 to L-type calcium channels. [3H]N6-cyclohexyl-adenosine to adenosine A1 and [3H]quinuclidinyl benzilate to muscarinic cholinergic receptor) were assayed using quantitative autoradiography. In the CA1 subfield, 2 h after ischemia, [3H]IP3, [3H]forskolin, and [3H]quinuclidinyl benzilate binding activities significantly decreased by 25, 17 and 13%, respectively, though no morphological abnormalities were obvious. Six hours after ischemia, the [3H]phorbol 12,13-dibutylate binding activity in the stratum oriens of the CA1 subfield increased by 15%. One day after ischemia, [3H]PN200-110 binding activity in this subfield decreased by 26%, and 7 days after ischemia, [3H]phorbol 12,13-dibutylate and [3H]N6-cyclohexyl-adenosine receptor binding activities decreased in this subfield. In particular, at 7 days after ischemia, [3H]IP3 binding activity in the CA1 subfield showed a complete decline. In the CA3 subfield, [3H]PN200-110 binding activity decreased 2 days after ischemia, and [3H]IP3 and [3H]N6-cyclohexyl-adenosine binding activities decreased 7 days after ischemia. In the dentate gyrus, the structure of which remained histologically intact after ischemic insult, [3H]IP3 and [3H]forskolin binding activities decreased 7 days after ischemia. In contrast, the [3H]phorbol 12,13-dibutylate binding activity increased in the molecular layer of the dentate gyrus 7 days after ischemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 subfield and that the histologically intact CA3 and dentate gyrus also shows modulated neuronal transmission after ischemia.
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PMID:Autoradiographic analysis of second messenger and neurotransmitter system receptors in the gerbil hippocampus following transient forebrain ischemia. 165 Feb 82


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