Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.1 (NADPH-diaphorase)
 3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested the hypothesis that high prostaglandin levels during the perinatal period might regulate brain nitric oxide synthase (nNOS) expression. nNOS and cyclooxygenase (COX)-2 mRNAs were higher in brain cortex and the periventricular area of newborn rats and pigs compared with adult brain. Nitric oxide synthase activity was also 2. 5- to 4-fold higher in newborn than in adult brain. Administration of nonselective COX inhibitor ibuprofen or COX-2 inhibitor nimesulide every 8 h for 24 h to newborn rats and pigs reduced prostaglandin levels and caused comparable reductions in nNOS mRNA, protein, and activity to levels of adults; COX inhibitor-induced changes were prevented by cotreatment with PGE2 analog, 16, 16-dimethyl-PGE2, and agonist for the EP3 receptor of PGE2, sulprostone, but not by PGI2 analog carbaprostacyclin, PGD2, EP1 receptor agonist 17-phenyl trinor-PGE2, and EP2 agonist butaprost. Concordant observations were made in vitro and revealed that nNOS expression (detected by NADPH diaphorase reactivity) mostly present in neurons of the deeper cortical layers was reduced by COX inhibitor, and this effect was prevented by EP3 agonist. In conclusion, high levels of PGE2 in neonatal brain contribute to the increased expression of nNOS by acting on EP3 receptors; this positive interaction between PGE2 and nNOS might be required physiologically for normal brain development.
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PMID:PGE2, via EP3 receptors, regulates brain nitric oxide synthase in the perinatal period. 984 70

Prostaglandin E2 (PGE2), the principal pro-inflammatory prostanoid, is known to play versatile roles in pain transmission via four PGE receptor subtypes, EP1-EP4. We recently demonstrated that continuous production of nitric oxide (NO) by neuronal NO synthase (nNOS) following phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS) and NMDA receptor NR2B subunits is essential for neuropathic pain. These phosphorylation and nNOS activity visualized by NADPH-diaphorase histochemistry were blocked by indomethacin, a PG synthesis inhibitor. To clarify the interaction between cyclooxygenase and nNOS pathways in the spinal cord, we examined the effect of EP subtype-selective agonists on NO production. NO formation was stimulated in the spinal superficial layer by EP1, EP3, and EP4 agonists. While the EP1- and the EP4-stimulated NO formation was markedly blocked by MK-801, an NMDA receptor antagonist, the EP3-stimulated one was completely inhibited by H-1152, a Rho-kinase inhibitor. Phosphorylation of MARCKS and NADPH-diaphorase activity stimulated by the EP3 agonist were also blocked by H-1152. These results suggest that PGE2 stimulates NO formation by Rho-kinase via EP3, a mechanism(s) different from EP1 and EP4.
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PMID:Rho-kinase mediates spinal nitric oxide formation by prostaglandin E2 via EP3 subtype. 1618 27

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.
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PMID:Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. 1619 Aug 98