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

---

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

Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl) glycine (DCGIV; 5 microM), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 microM), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 microM) was combined with a cell-permeant PKA inhibitor H-89 (10 microM), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 microM), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 microM), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6-cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 microM), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity.
...
PMID:Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses. 1632 19

Feeding in codling moth caterpillars was induced by the general glutamate receptor activator monosodium glutamate (MSG) and by three different mGluR agonists known to specifically stimulate different classes of vertebrate metabotropic glutamate receptors, including: (1S,3R)-ACPD, which stimulates group I mGluRs (2R,4R)-APDC, which stimulates group II mGluRs and L-AP4, which stimulates some group III mGluRs. Experiments exposing larvae to combinations of specific mGluR agonists and specific signal transduction modulators suggest that each tested mGluR uses a different signaling pathway. First, feeding stimulatory effects of (1S,3R)-ACPD were abolished by phospholipase C inhibitor, U 73122, but remained unaffected by adenylate cyclase activator, NKH 477, or phosphodiesterase inhibitor, Rolipram. Second, (2R,4R)-APDC induced feeding in presence of U 73122 or Rolipram, but lost its feeding stimulatory effects in presence of NKH 477. Finally, L-AP4 did not induce feeding in presence of Rolipram, but maintained its feeding stimulatory effects in presence of U 73122 or NKH 477. The activity of the general glutamate receptor activator MSG was abolished by NKH 477, and Rolipram. U 73122 did not affect MSG-stimulated feeding. These results suggest that transduction of MSG taste in the codling moth caterpillar relies mostly on cAMP-dependent signaling pathways.
...
PMID:Effect of metabotropic glutamate receptor agonists and signal transduction modulators on feeding by a caterpillar. 1636 14

For a number of patients with bipolar disorder, current pharmacotherapy is generally insufficient. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability, and significant medical and psychiatric comorbidity. Drug development for bipolar disorder may occur through one of two approaches: the first is by understanding the therapeutically relevant biochemical targets of currently effective medications. Two promising direct targets of lithium and valproate are glycogen synthase kinase-3 and histone deacetylase. The second path results from our understanding that severe mood disorders, although not classical neurodegenerative disorders, are associated with regional impairments of structural plasticity and cellular resilience. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid potentiators, cyclic adenosine monophosphate phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.
...
PMID:Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. 1648 91

Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with chronic or acute liver disease. We review here some recent advances in the study, in animal models, of the mechanisms involved in the impairment in intellectual function in hepatic encephalopathy. These studies show that the function of the glutamate-nitric oxide-cGMP pathway is impaired in brain in vivo in rats with chronic hyperammonemia or liver failure and from patients died in hepatic encephalopathy. This impairment leads to a reduced extracellular concentration of cGMP in the cerebellum and is associated with reduced learning ability in these animal models. Moreover, learning ability of hyperammonemic rats was restored by increasing cGMP by: (1) continuous intracerebral administration of zaprinast, an inhibitor of the cGMP-degrading phosphodiesterase, (2) chronic oral administration of sildenafil, an inhibitor of the phosphodiesterase that crosses the blood-brain barrier and (3) continuous intracerebral administration of cGMP. The data summarized indicate that impairment of learning ability in rats with chronic liver failure or hyperammonemia is due to impairment of the glutamate-nitric oxide-cGMP pathway. Moreover, increasing extracellular cGMP by pharmacological means may be a new therapeutic approach to improve cognitive function in patients with hepatic encephalopathy.
...
PMID:Role of extracellular cGMP and of hyperammonemia in the impairment of learning in rats with chronic hepatic failure. Therapeutic implications. 1649 13

Natriuretic peptides (NP) and the corresponding receptors are present in the rodent spinal cord. We have studied the structures which respond to atrial natriuretic peptide, brain natriuretic peptide, or C-type natriuretic peptide with an increased synthesis of cGMP. NP-responsive cGMP-producing structures were observed in laminae I-III, and X, and in addition in ependymal cells, astrocytes and a subpopulation of dorsal root ganglion cells. As the cGMP concentration is controlled by the rate of synthesis and the rate of breakdown by phosphodiesterases, we studied NP-responsive structures in spinal cord slices incubated in the presence of different phosphodiesterase inhibitors. We studied EHNA and BAY 60-7550 as selective PDE2 inhibitors, sildenafil as a selective PDE5 inhibitors, dipyridamole as a mixed type PDE5 and PDE10 inhibitor, rolipram as a PDE4 inhibitor, and SCH 81566 as a selective PDE9 inhibitor. Double immunostainings showed that cGMP-IR colocalized partial with the vesicular acetylcholine transporter molecule in lamina X, with Substance P in a subpopulation of neuronal fibers situated dorsolateral, and with a subpopulation of CGRP-IR dorsal root ganglion neurons. Colocalization of cGMP-IR was absent with parvalbumin, synaptophysin, and the vesicular transporter molecules for GABA and glutamate. It is concluded that NPs in the spinal cord are probably involved in integrating intersegmental sensory processing in the spinal cord although the greater part of the NP-responsive cGMP-producing fibers could not be characterized. PDE2, 5, and 9 are involved in regulating NP-stimulated cGMP levels in the spinal cord. NPs may have a role in regulating cerebrospinal fluid homeostasis.
...
PMID:ANP-mediated cGMP signaling and phosphodiesterase inhibition in the rat cervical spinal cord. 1662 44

NO-responsive, cGMP-producing structures are abundantly present in the cervical spinal cord. NO-mediated cGMP synthesis has been implicated in nociceptive signaling and it has been demonstrated that cGMP has a role establishing synaptic connections in the spinal cord during development. As cGMP levels are controlled by the activity of soluble guanylyl cyclase (synthesis) and the phosphodiesterase (PDE) activity (breakdown), we studied the influence of PDE activity on NO-stimulated cGMP levels in the rat cervical spinal cord. cGMP-immunoreactivity (cGMP-IR) was localized in sections prepared from slices incubated in vitro. A number of reported PDE isoform-selective PDE inhibitors was studied in combination with diethylamineNONOate (DEANO) as a NO-donor including isobutyl-methylxanthine (IBMX) as a non-selective PDE inhibitor. We studied 8-methoxy-IBMX as a selective PDE1 inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and BAY 60-7550 as selective PDE2 inhibitors, sildenafil as a selective PDE5 inhibitor, dipyridamole as a mixed type PDE5 and PDE10 inhibitor, rolipram as a PDE4 inhibitor, and SCH 81566 as a selective PDE9 inhibitor. cGMP-IR structures (nerve fibers, axons, and terminals) were characterized using the following neurochemical markers: vesicular transporter molecules for acetylcholine, GABA, and glutamate (type 1 and type 2), parvalbumin, glutamate transporter molecule EAAT3, synaptophysin, substance P, calcitonin gene-related peptide, and isolectin B4. Most intense cGMP-IR was observed in the dorsal lamina. Ventral motor neurons were devoid of cGMP-IR. cGMP-IR was observed in GABAergic, and glutamatergic terminals in all gray matter laminae. cGMP-IR was abundantly colocalized with anti-vesicular glutamate transporter 2 (vGLUT2), however not with the anti-vesicular glutamate transporter 1 (vGLUT1), suggesting a functional difference between structures expressing vGLUT1 or vGLUT2. cGMP-IR did not colocalize with substance P- or calcitonin-gene related peptide-IR structures, however did partially colocalize with isolectin B4 in the dorsal horn. cGMP-IR in cholinergic structures was observed in dorsal root fibers entering the spinal cord, occasionally in laminae 1-3, in laminae 8 and 9 in isolated boutons and in the C-type terminals, and in small cells and varicosities in lamina 10. This latter observation suggests that the proprioceptive interneurons arising in lamina 10 are also NO-responsive. No region-specific nor a constant co-expression of cGMP-IR with various neuronal markers was observed after incubation of the slices with one of the selected PDE inhibitors. Expression of the mRNA of PDE2, 5, and 9 was observed in all lamina. The ventral motor neurons and the ependymal cells lining the central canal expressed all three PDE isoforms. Incubation of the slices in the presence of IBMX, DEANO in combination with BAY 41-2272, a NO-independent activator of soluble guanylyl cyclase, provided evidence for endogenous NO synthesis in the slice preparations and enhanced cGMP-IR in all lamina. Under these conditions cGMP-IR colocalized with substance P in a subpopulation of substance P-IR fibers. It is concluded that NO functions as a retrograde neurotransmitter in the spinal cord but that also postsynaptic structures are NO-responsive by producing cGMP. cGMP-IR in a subpopulation of isolectin B4 positive fibers and boutons is indicative for a role of NO-cGMP signaling in nociceptive processing. cGMP levels in the spinal cord are controlled by the concerted action of a number of PDE isoforms, which can be present in the same cell.
...
PMID:The role of phosphodiesterase isoforms 2, 5, and 9 in the regulation of NO-dependent and NO-independent cGMP production in the rat cervical spinal cord. 1662 45

1. Glutamate-NMDA receptor excitotoxicity and oxidative stress are two common mechanisms associated with most neurodegenerative diseases. We hypothesize that the vital state of neurons is regulated in part by two key transcription factors, CREB and NF-kappaB. To test this hypothesis we used hippocampal-entorhinal cortex slice cultures. 2. Glutamate neurotoxicity and oxidative stress neurotoxicity, using hydrogen peroxide (H(2)O(2)) are both associated with a decrease in CREB DNA binding and an increase in NF-kappaB DNA binding. 3. Agents that modulate CREB and NF-kappaB DNA-binding activity alter neurotoxicity. Rolipram, a phosphodiesterase IV inhibitor, increased CREB DNA binding activity and decreased toxicity, whereas TNFalpha, increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). Ethanol decreased CREB and increased NF-kappaB DNA-binding activity and increased neurotoxicity to both glutamate and H(2)O(2). 4. Brain-derived neurotrophic factor (BDNF) is a transcriptionally regulated trophic factor whose expression follows sensitivity to toxicity suggesting it is one of the transcriptionally regulated factors that contributes to neuronal vitality secondary to the balance of CREB-NF-kappaB-activated transcription. Together these studies suggest that neurotoxicity through glutamate-NMDA receptors or oxidative stress is dependent upon CREB and NF-kappaB DNA transcription that regulates vitality of neurons.
...
PMID:CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. 1663 91

Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
...
PMID:SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. 1695 62

Hydrogenobacter thermophilus TK-6, a thermophilic and obligately chemoautotrophic bacterium, assimilates ammonium using glutamine synthetase (GS). GS was purified using three chromatography steps. The purified GS was found to belong to GS type I on the basis of its subunit composition and molecular weight. The Mg2+ -dependent activity of this GS significantly increased after incubation with phosphodiesterase, indicating that GS is subject to adenylyl/deadenylyl regulation, a posttranslational modification system reported mainly among enterobacteria. The degree of this posttranslational modification changed depending on growth phase, confirming that adenylyl/deadenylyl regulation functions in vivo. Interestingly, the Km for glutamate of H. thermophilus GS was significantly higher than those of other organisms, suggesting that GS activity is affected by intracellular glutamate concentration.
...
PMID:Purification and properties of glutamine synthetase from Hydrogenobacter thermophilus TK-6. 1711 77

Fuel stimulation of insulin secretion from pancreatic beta-cells is thought to be mediated by metabolic coupling factors that are generated by energized mitochondria, including protons, adenine nucleotides, and perhaps certain amino acids (AA), as for instance aspartate, glutamate, or glutamine (Q). The goal of the present study was to evaluate the role of such factors when insulin release (IR) is stimulated by glucose or AA, alone or combined, using (31)P, (23)Na and (1)H NMR technology, respirometry, and biochemical analysis to study the metabolic events that occur in continuously superfused mouse beta-HC9 cells contained in agarose beads and enhanced by the phosphodiesterase inhibitor IBMX. Exposing beta-HC9 cells to high glucose or 3.5 mM of a physiological mixture of 18 AA (AAM) plus 2 mM glutamine caused a marked stimulation of insulin secretion associated with increased oxygen consumption, cAMP release, and phosphorylation potential as evidenced by higher phosphocreatine and lower P(i) peak areas of (31)P NMR spectra. Diazoxide blocked stimulation of IR completely, suggesting involvement of ATP-dependent potassium (K(ATP)) channels in this process. However, levels of MgATP and MgADP concentrations, which regulate channel activity, changed only slowly and little, whereas the rate of insulin release increased fast and very markedly. The involvement of other candidate coupling factors was therefore considered. High glucose or AAM + Q increased pH(i). The availability of temporal pH profiles allowed the precise computation of the phosphate potential (ATP/P(i) x ADP) in fuel-stimulated IR. Intracellular Na+ levels were greatly elevated by AAM + Q. However, glutamine alone or together with 2-amino-2-norbornanecarboxylic acid (which activates glutamate dehydrogenase) decreased beta-cell Na levels. Stimulation of beta-cells by glucose in the presence of AAM + Q (0.5 mM) was associated with rising cellular concentrations of glutamate and glutamine and strikingly lower aspartate levels. Methionine sulfoximine, an inhibitor of glutamine synthetase, blocked the glucose enhancement of AMM + Q-induced IR and associated changes in glutamine and aspartate but did not prevent the accumulation of glutamate. The results of this study demonstrate again that an increased phosphate potential and a functional K(ATP) channel are essential for metabolic coupling during fuel-stimulated insulin release but illustrate that determining the identity and relative importance of all participating coupling factors and second messengers remains a challenge largely unmet.
...
PMID:Metabolic and ionic coupling factors in amino acid-stimulated insulin release in pancreatic beta-HC9 cells. 1726 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---