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)

Homer is a scaffold protein that binds glutamate receptor complexes and actin cytoskeleton in postsynapses. The present study analyzed developmental changes in subcellular localization of Homer proteins in cultured hippocampal neurons. All three Homer family proteins, Homer 1b/c, Cupidin/Homer 2, and Homer 3, not only form heteromeric coclusters, but also localize close to the NMDA receptor complex including the NR2B subunit and PSD95 throughout dendritic and synaptic differentiation. Synaptic clustering of Homer proteins is enhanced by simultaneous blockade of NMDA receptor and cAMP phosphodiesterase activities, as is clustering of NMDA receptors. Homer proteins colocalize with actin-cytoskeletal proteins F-actin and Drebrin partially during the middle stage and to a greater extent in the late stage, and with the GluR1 subunit of AMPA receptors only in the late stage. Clustering sites of Homer are not synaptic in early-middle stages, but become synaptic in the late stage, as deduced from synaptic targeting of Bassoon, Synaptophysin, and N-cadherin. Our results indicate a coincidence in dendritic clustering in addition to developmental and activity-regulated synaptic targeting between Homer and the NMDA receptor complex.
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PMID:Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons. 1267 29

The presynaptic regulation of striatal glutamate transmission was investigated using D-[3H]aspartate and mouse striatal slices. Functional changes in voltage-dependent and glutamate receptor-gated ion channels were elicited by pharmacologically modifying intracellular cyclic AMP formation via G-protein-coupled receptor stimulation. The kainate (KA)-evoked release was potentiated by the stimulatory G-protein (G(s))-coupled beta-adrenoceptor agonist isoproterenol (ISO) in a concentration-dependent manner. This effect was mimicked by the specific calmodulin (CaM) antagonists trifluoperazine and calmidazolium. Tetrodotoxin (TTX), a blocker of Na(+) channels, did not affect the basal release but inhibited to the same degree the releases evoked by kainate alone and by kainate and isoproterenol together. Vinpocetine, a blocker of voltage-dependent Na(+) channels, did not alter the basal or the evoked release. The Na(+) channel activator veratridine enhanced the basal release in a concentration-dependent manner and isoproterenol attenuated this effect. The opposite effects of isoproterenol on the kainate- and veratridine-evoked releases may reflect prevention of the cyclic AMP-protein kinase A (PKA) phosphorylation cascade in striatal glutamatergic signal transduction. In addition, the calmidazolium-induced potentiation of kainate-evoked release was thwarted by LY354740 and L-2-amino-4-phosphonobutanoate, agonists of the inhibitory G-protein (G(i))-coupled metabotropic group II and III glutamate receptors (mGluRs). Vinpocetine, which inhibits the CaM-dependent phosphodiesterase (PDE1), was likewise inhibitory. In turn, selective agonists and antagonists of the G(q)-protein-coupled group I mGluRs and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) and (RS)-1-aminoindan-1,5-dicarboxylate (AIDA), which modulate the intracellular Ca(2+) levels, did not alter the kainate-evoked release. The beta-adrenoceptor-mediated cyclic AMP accumulation seems to downregulate Na(+) channels but to enhance glutamate release by means of upregulation of kainate receptors. This regulation of presynaptic ligand- and voltage-gated ion channels is affected by the cAMP-protein kinase A-dependent phosphorylation cascade and controlled by G(i)-protein-coupled mGluRs.
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PMID:Cyclic AMP-mediated regulation of striatal glutamate release: interactions of presynaptic ligand- and voltage-gated ion channels and G-protein-coupled receptors. 1274 88

The major part of hippocampal innervation is glutamatergic, regulated by inhibitory GABA-releasing interneurons. The modulation of [(3)H]GABA release by ionotropic and metabotropic glutamate receptors and by nitric oxide was here characterized in superfused mouse hippocampal slices. The ionotropic glutamate receptor agonists kainate, N-methyl-D-aspartate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate potentiated the basal GABA release. These effects were blocked by their respective antagonists 6-nitro-7-cyanoquinoxaline-2,3-dione (CNQX), dizocilpine and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide (NBQX), indicating receptor-mediated mechanisms. The NO-generating compounds S-nitroso-N-acetylpenicillamine (SNAP), sodiumnitroprusside and hydroxylamine enhanced the basal GABA release. Particularly the sodiumnitroprusside-evoked release was attenuated by the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) and the inhibitor of soluble guanylyl cyclase 1H-(1,2,4)oxadiazolo(4,3a)quinoxalin-1-one (ODQ), indicating the involvement of the NO/cGMP pathway. This inference is corroborated by the enhancing effect of zaprinast, a phosphodiesterase inhibitor, which is known to increase cGMP levels. The K(+)-stimulated hippocampal GABA release was reduced by the groups I and III agonists of metabotropic glutamate receptors (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) and L-(+)-2-amino-4-phosphonobutyrate (L-AP4), which effects were abolished by their respective antagonists (RS)-1-aminoindan-1,5-dicarboxylate (AIDA) and (RS)-2-cyclopropyl-4-phosphonophenylglycine (CPPG), again indicating modification by receptor-mediated mechanisms.
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PMID:Characteristics of GABA release modified by glutamate receptors in mouse hippocampal slices. 1274 91

We have investigated the functional relationships between NMDA receptors and the NOS/sGC system in the rat pre-frontal cortex in vivo by microdialysis. cGMP basal levels were sensitive to NOS or sGC inhibitors (L-NARG or ODQ) or NO donors (SNAP) when enzymatic breakdown was blocked by the phosphodiesterase inhibitor IBMX, indicating that basal cGMP production derives, at least in part, from the NOS/sGC pathway activity and that the pre-frontal cortex possesses a very efficient degradation system for cGMP. The glutamate receptor agonist NMDA did not alter extracellular cGMP either in absence or presence of IBMX. cGMP was not augmented when NMDA was co-infused with the NOS substrate L-arginine, the glycine site agonist d-serine or the glutamate receptor agonist AMPA. Interestingly, the selective GABA(A) receptor antagonist bicuculline enhanced cGMP production, revealing that the cortical NOS/sGC system is tonically inhibited by endogenous GABA. However, in the presence of bicuculline, NMDA did not increase extracellular cGMP. In the presence of bicuculline, blockade of 5-HT1/2 receptors, known to inhibit the NMDA/NOS/sGC pathway, with the antagonist methiothepin did not unmask cGMP elevations by NMDA. Thus, it would seem that NMDA receptors do not regulate cortical NOS/sGC activity that, on the other hand, is modulated by endogenous GABA acting at GABA(A) receptors.
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PMID:GABA(A), but not NMDA, receptors modulate in vivo NO-mediated cGMP synthesis in the rat cerebral cortex. 1497 71

The novel type of neurotransmitter/neuromodulator nitric oxide (NO) is linked to activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptors and has been shown to modify transmitter release in the brain. The inhibitory neuromodulator adenosine has been thought to act as an endogenous neuroprotectant against cerebral ischemia and neuronal damage. The effects of NO-generating compounds on the release of preloaded [3H]adenosine from hippocampal slices from developing (7-day-old) and adult (3-month-old) mice were investigated, using a superfusion system, under normal conditions and in vitro ischemia. The release of adenosine was markedly potentiated at both ages by the NO-producing compounds S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and hydroxylamine. The evoked releases were reduced by the NO synthase inhibitors nitroarginine and 7-nitroindazole at both ages. They were also reduced by the inhibitor of soluble guanylyl cyclase 1H-(1,2,4-oxadiazolo(4,3a)quinoxalin-1-one (ODQ) in adults, indicating that the NO/cGMP pathway is involved in this release. Release of adenosine was also evoked when the cGMP levels were increased by superfusing slices with the phosphodiesterase inhibitor zaprinast. The markedly enhanced adenosine release under ischemic conditions was further potentiated by the ionotropic glutamate receptor agonists and NO-generating compounds, whereas zaprinast and ODQ had no effect, rendering unlikely the involvement of cGMP in the ischemic release. Moreover, NO was able to provoke substantial release of adenosine in the presence of NMDA under both normal and ischemic conditions, which could significantly add to the neuroprotective potential of this neuromodulator in both adult and developing hippocampus.
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PMID:Involvement of nitric oxide in adenosine release in the developing and adult mouse hippocampus. 1499 81

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.
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PMID:Effect of metabotropic glutamate receptor agonists and signal transduction modulators on feeding by a caterpillar. 1636 14

The release of the inhibitory neurotransmitter GABA is generally enhanced under potentially cell-damaging conditions. The properties and regulation of preloaded [3H]GABA release from mouse hippocampal slices were now studied in free radical-containing medium in a superfusion system. Free radical production was induced by 0.01% of H2O2 in the medium. H2O2 markedly potentiated GABA release, which was further enhanced about 1.5-fold by K+ stimulation (50 mM). In Ca2+-free media this stimulation was not altered, indicating that the release was mostly Ca2+-independent. Moreover, omission of Na+ increased the release, suggesting that it is mediated by Na+-dependent transporters operating outwards, a conception confirmed by the enhancement with GABA homoexchange. Inhibition of the release with the ion channel inhibitors diisothiocyanostilbene-2,2'-disulphonate and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate indicates that Cl(-) channels also participate in the process. This release was not modified by the adenosine receptor (A1 and A2a) agonists and ionotropic glutamate receptor agonists kainate, N-methy-D: -aspartate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, whereas the agonists of metabotropic glutamate receptors of group I [(S)-3,5-dihydroxyphenylglycine] and of group II [(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate] enhanced it by receptor-mediated mechanisms, the effects being abolished by their respective antagonists. The group III agonist L+-2-amino-4-phosphonobutyrate reduced the evoked GABA release, but this was not affected by the antagonist. Furthermore, the release was reduced by activation of protein kinase C by 4 beta-phorbol 12-myristate 13-acetate and by inhibition of tyrosine kinase by genistein and of phoshoplipase by quinacrine. On the other hand, increasing cGMP levels with the phosphodiesterase inhibitor zaprinast, selective for PDE5, 6 and 9, and NO production with the NO-generating compounds hydroxylamine, sodium nitroprusside and S-nitroso-N-penicillamine enhanced the release. The regulation of GABA release induced by free radical production proved thus to be rather complex. Under potentially cell-damaging conditions, the potentiation of GABA release may be a mechanism to counteract hyperactivity and reduce the effects of excitatory amino acid release. On the other hand, reduction of GABA release could be harmful and contribute to excitotoxic damage and neuronal degeneration.
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PMID:Characteristics of GABA release induced by free radicals in mouse hippocampal slices. 1771 30

In nonprimate mammals, the dorsal cochlear nucleus (DCN) is thought to play a role in the orientation of the head toward sounds of interest by integrating acoustic and somatosensory information. Humans and higher primates might not use this system because of reported phylogenetic changes in DCN cytoarchitecture [Moskowitz N (1969) Comparative aspects of some features of the central auditory system of primates. Ann N Y Acad Sci 167:357-369; Moore JK, Osen KK (1979) The cochlear nuclei in man. Am J Anat 154:393-418; Moore JK (1980) The primate cochlear nuclei: loss of lamination as a phylogenetic process. J Comp Neurol 193:609-629]. In this study, we re-evaluated this question from a comparative perspective and examined the rhesus monkey (cercopithecoid primate) using more sensitive probes and higher resolution imaging methods. We used electron microscopy to identify parallel fibers and their synapses, and molecular markers to determine that primates exhibit the main components of excitatory neurotransmission as other mammals. We observed that characteristics of the monkey molecular layer resembled what has been reported for nonprimates: (1) immunohistochemistry revealed many unmyelinated, thin axons and en passant glutamatergic synapses on dendritic spines; (2) immunohistochemistry for phosphodiesterase (PDE10A) showed the nuclei of granule cells distributed in the external molecular layer and the deep layers in the DCN; (3) antibodies for the inositol trisphosphate receptor (IP3r) and calbindin immunostained cartwheel cells; (4) postembedding immunogold labeling revealed synaptic expression of AMPA and delta glutamate receptor subunits on spines in parallel fiber endings; and (5) parallel fibers use vesicular glutamate transporter 1 (VGLUT1) to package glutamate into the synaptic vesicles and to mediate glutamate transport. These observations are consistent with the argument that the rhesus monkey DCN has neuronal features similar to those of other nonprimate mammals.
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PMID:Revealing the molecular layer of the primate dorsal cochlear nucleus. 1822 48

In the brain stem glycine is associated with multiple sensory and visceral regulations, being involved in, for instance, cardiovascular, respiratory and auditory functions. We here studied the mechanisms of the release of preloaded [(3)H]glycine from mouse brain stem slices in a superfusion system. A depolarizing concentration of K(+) ions (50 mM) evoked glycine release, but in the absence of Ca(2+) the effect was attenuated, indicating that a part of the evoked release represents Ca(2+)-dependent exocytosis. The Ca(2+)-independent release was enhanced by omission of Na(+) and Cl(-). The stimulatory effect of extracellular glycine confirmed the involvement of transporters functioning in a reverse direction. A part of the release is mediated by Na(+) and Cl(-) channels, since it was inhibited by the inhibitors of these, riluzole and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonate, respectively. Glycine release was potentiated by the activation of protein kinase C and diminished by increasing cyclic guanosine monophosphate levels with a phosphodiesterase inhibitor, zaprinast. The release was also modulated by the phospholipase inhibitor quinacrine and the tyrosine kinase inhibitor genistein. Adenosine A(1) receptors likewise regulate glycine release, since it was enhanced by their agonist R(-)N(6)-(2-phenylisopropyl)adenosine, which effect was blocked by the antagonist 8-cyclopentyl-1,3-dipropylxanthine. The ionotropic glutamate receptor agonists N-methyl-D: -aspartate, kainate and 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate failed to have any effects contrary to their effects in higher brain regions, e.g., in the hippocampus. The group I and III metabotropic glutamate receptor agonists (S)-3,5-dihydroxyphenylglycine and O-phospho-L: -serine, respectively, increased the release in a receptor-mediated manner. Glycine release in the brain stem was also markedly enhanced by cell-damaging conditions, including hypoxia, hypoglycemia and ischemia.
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PMID:Mechanisms of glycine release in mouse brain stem slices. 1860 Apr 48

GPR35 is a Gi/o- and G16-coupled receptor abundantly expressed in gastrointestinal tissues and immune cells. Kynurenic acid (a tryptophan metabolite and ionotropic glutamate receptor antagonist) and zaprinast (a phosphodiesterase inhibitor) are GPR35 agonists. Here, we show that the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) is also a GPR35 agonist. NPPB activates the GPR35-Gi/o and GPR35-G16 pathways in human embryonic kidney 293 (HEK293) cells and induces intracellular calcium mobilization in a concentration-dependent manner in HEK293 cells coexpressing human, rat or mouse GPR35 and the chimeric G protein G(qi5). These results suggest a novel pharmacological activity of NPPB and will provide useful information to search for more potent and selective GPR35 agonists.
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PMID:5-Nitro-2-(3-phenylpropylamino)benzoic acid is a GPR35 agonist. 1881 9


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