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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clonazepam at two doses of 1 mg/kg i.p. significantly decreased 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents in the rat caudatus and cortex but not so in the olfactory tubercle, septum and hypothalamus. The drug decreased dopamine (DA) turnover rate in the caudatus, but did not inhibit tyrosine hydroxylase activity. The drug significantly enhanced stereotyped behavior induced by apomorphine and d-methamphetamine. Clonazepam enhanced apomorphine-induced decrease in striatal HVA, and cortical DOPAC and HVA contents, and d-methamphetamine-induced decrease in cortical DOPAC content. Reserpine pretreatment did not affect apomorphine-induced stereotypy and its enhancement with clonazepam. The drug did not activate adenylate cyclase nor DA-sensitive adenylate cyclase in the striatal homogenates and did not change cyclic AMP content in the caudatus. The drug inhibited phosphodiesterase activity in caudate and cortical homogenates but not in vivo. Clonazepam did not alter ChAc and AChE activities in the caudatus, 6 other cerebral regions and the spinal area. Clonazepam also decreased NE turnover in the caudatus and 5-HIAA contents in the brainstem area. These neurochemical and behavioral effects of clonazepam indicate probable postjunctional DA stimulation in the striatum and cortex of the type not linked with adenylate cyclase and phosphodiesterase but probably due to activation of inhibitory gamma-amino butyric acid (GABA) neurons on the strio-nigral pathway.
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PMID:[Influence of clonazepam, an anticonvulsant benzodiazepine drug, on the rat brain monoamine containing neurons especially on dopaminergic neurons (author's transl)]. 20 28

Odors activate at least two distinct transduction pathways in lobster olfactory receptor cells that, respectively, excite and inhibit the cell. Data presented suggest that odors selectively activate the inhibitory conductance through the second messenger cAMP. Not all cells support both odor-evoked excitatory and inhibitory conductances; in the current investigation, about 50% of the cells tested were inhibited by odors. In the majority of cells that, as a group, support an inhibitory response to odor stimulation, activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine (IBMX) elicits an outward current with a time course similar to that of odor-evoked outward currents. The membrane-permeant cyclic nucleotide analogs 8-Br-cAMP and 8-Br-cGMP have a similar effect. Forskolin and IBMX enhance the magnitude of odor-evoked outward currents when the drug and the odor are copresented to the cell. In contrast, these same drugs have little or no effect on cells that, as a group, fail to support an inhibitory response to odor stimulation. This study provides the first direct evidence implicating cAMP in olfactory transduction in an invertebrate and contrasts with similar studies in vertebrates that have implicated cAMP as a second messenger mediating excitation.
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PMID:Cyclic nucleotides mediate an odor-evoked potassium conductance in lobster olfactory receptor cells. 138 77

The olfactory mucosa of the frog was isolated, folded (the outer, ciliated side faced outward), and separately superfused with Ringers solution on each side. A small number of sensory cilia (one to three) were pulled into the orifice of a patch pipette and current was recorded from them. Fast bipolar current transients, indicating the generation of action potentials by the receptor cells, were transmitted to the pipette, mainly through the ciliary capacitance. Basal activity was near 1.5 spikes s-1. Exposure of apical membrane areas outside of the pipette to permeant analogues of cyclic nucleotides, to forskolin, and to phosphodiesterase inhibitors resulted in a dose-dependent acceleration of spike rate of all cells investigated. Values of 10-20 s-1 were reached. These findings lend further support to the notion that cyclic nucleotides act as second messengers, which cause graded membrane depolarization and thereby a graded increase in spike rate. The stationary spike rate induced by forskolin was very regular, while phosphodiesterase inhibitors caused (in the same cell) an irregular pattern of bursts of spikes. The response of spike rate was phasic-tonic in the case of strong stimulation, even when elicited by inhibitors of phosphodiesterase or by analogues of cyclic nucleotides that are not broken down by the enzyme. Thus, one of the mechanisms contributing to desensitization appears to operate at the level of the nucleotide-induced ciliary conductance. However, desensitization at this level was slow and only partial, in contrast to results obtained with isolated, voltage-clamped receptor cells.
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PMID:Current recording from sensory cilia of olfactory receptor cells in situ. I. The neuronal response to cyclic nucleotides. 170 55

Theophylline and 3-isobutyl-1-methylxanthine, two cyclic nucleotide phosphodiesterase inhibitors, when fed to wild-type Drosophila adults, cause the rapid decay of learning index after training in a shock-odor learning paradigm. The drugs practically do not affect the olfactory acuity of flies, hence they influence the learning/memory process itself. The time courses of memory decay resemble those of the memory mutants rutabaga and amnesiac and, to a lesser extent, dunce2 and dunceM11. Theophylline further deteriorates the learning performance of dunceM11. Biochemical characterization of the inhibition of the two major phosphodiesterase isoenzymes in Drosophila by theophylline predicts only a slight inhibition of these enzymes in vivo, in accordance with the unchanged level of cAMP in wild-type fly heads during drug feeding. 8-Phenyltheophylline, an adenosine receptor antagonist in mammals, slightly retards memory decay in the wild-type. It is suggested that alkylxanthines induce memory decay in Drosophila by interfering with cAMP dynamics at more than one point of its metabolism.
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PMID:On the pharmacological phenocopying of memory mutations in Drosophila: alkylxanthines accelerate memory decay. 172 65

Drosophila dunce (dnc) flies are defective in learning and memory as a result of lesions in the gene that codes for a cAMP-specific phosphodiesterase (PDE). Antibodies to the dnc PDE showed that the most intensely stained regions in the adult brain were the mushroom body neuropil--areas previously implicated in learning and memory. In situ hybridization demonstrated that dnc RNA was enriched in the mushroom body perikarya. The mushroom bodies of third instar larval brains were also stained intensely by the antibody, suggesting that the dnc PDE plays an important role in these neurons throughout their development. The role of the dnc PDE in mushroom body physiology is discussed, and a circuit model describing a possible role of the mushroom bodies in mediating olfactory learning and memory is presented.
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PMID:The cyclic AMP phosphodiesterase encoded by the Drosophila dunce gene is concentrated in the mushroom body neuropil. 184 82

The effect of cyclic AMP (cAMP) analogs and phosphodiesterase (PDE) inhibitors on neurite outgrowth was studied in explant cultures of olfactory neurons. Nasal pits from 5- or 6-day-old chick embryos were minced, explanted into culture dishes, and grown in a serum-free medium. One of the cyclic AMP analogs, dibutyryl cyclic AMP (dbcAMP) or 8-bromo-cyclic AMP (8-Br-cAMP), or one of the PDE inhibitors, theophylline or isobutylmethylxanthine (IBMX), was added to the culture medium. The explants were examined for neurite outgrowth after 2 days in vitro. Db-cAMP increased the number of explants expressing neurites by 25-35% over control cultures, whereas 8-Br-cAMP had essentially no effect at the same concentrations. Addition of dibutyryl cyclic GMP (dbcGMP) gave no increase in neurite outgrowth, thus indicating that the effect of enhancing neuritic growth is specific to cAMP and not cyclic nucleotides in general. The resulting increase in neurite outgrowth is due to the cyclic nucleotide component of dbcAMP, since both IBMX and theophylline, which elevate intracellular cAMP, also increased neurite outgrowth significantly. When forskolin was added to the culture medium, there was a trend to increased neurite outgrowth; this was significantly enhanced when a subthreshold concentration of theophylline was added in addition to the forskolin.
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PMID:The effect of cyclic AMP on neuritic outgrowth in explant cultures of developing chick olfactory epithelium. 246 49

The activity of glycerophosphorylcholine phosphodiesterases was determined in the mesencephalon, diencephalon, cerebral hemispheres, cerebellum and olfactory bulb during postnatal development from P5 to P70 of rat brain. These activities are low and gradually increase to near adult levels by the end of the first postnatal month similar to that for CNPase activity. This is in accord with glycerophosphorylcholine choline phosphate phosphodiesterase being present in the myelin membrane.
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PMID:Regional and developmental estimations of glycerophosphorylcholine phosphodiesterase activities in rat brain. 254 Sep 50

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.
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PMID:Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. 255 65

In the rat olfactory tissue the existence of soluble and membrane-bound forms of cyclic nucleotide phosphodiesterase (PDE) with quite similar kinetic parameters was demonstrated (KM = 220 and 200 microM, VMaX = 10 and 7 nmoles cAMP/mg protein per minute, respectively). 17 beta-estradiol (10(-7)-10(-5) M) decreased the soluble PDE activity by 25%, whereas non-hydrolysable GTP analogue (Gpp (NHp)) abolished their effect. On the other hand, this analogue in a dose-dependent manner inhibited the specific binding of 3H-estradiol to cytosolic receptors. The data indicate possible functional interrelations between the cytosolic estradiol receptors, GTP-binding proteins and PDE in the olfactory tissue which is a target organ for steroid hormones.
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PMID:[Cyclic nucleotide phosphodiesterase of the olfactory membrane in rats: its distribution and possible connection with the estradiol receptor]. 282 98

The activity of glycerophosphorylcholine cholinephosphodiesterase was quantified in the diencephalon, mesencephalon, cerebral hemispheres, olfactory bulb and cerebellum postnatally for P5 until P70 of rat brain. The initially low activities gradually increase to adult levels by P30. The patterns of regional development are reminescent of those previously described for choline acetyltransferase activity. It is suggested that these may be functionally linked in neuronal cells. The activity of glycerophosphorylcholine phosphocholine phosphodiesterase was also determined and found to be similar although only one half as active as the enzyme liberating choline. The present experiments show that both the GPC phosphocholine phosphodiesterase and the GPC choline phosphodiesterase are regionally and developmentally regulated in rat brain.
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PMID:Developmental and regional quantitation of glycerophosphorylcholine phosphodiesterase activities in rat brain. 285 7


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