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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The urothelium plays a sensory role responding to deformation of the bladder wall; this involves the release of adenosine trisphosphate (ATP) and nitric oxide (NO), which affect afferent nerve discharge and bladder sensation. The urothelial cells responsible for producing ATP and NO and the cellular targets, other than afferent nerves, for ATP and NO remain largely unexplored. Sub-urothelial interstitial cells (SU-ICs) lie immediately below the urothelium and respond to NO with a rise in cGMP. To determine which cells might target SU-ICs by producing NO, areas of dome, lateral wall and base wall were treated with isobutyl-methyl-xanthine, exposed to the NO donor diethylamino NONOate and then fixed for immunohistochemistry. Surface urothelial cells (SUCs) in the base and dome expressed neuronal nitric oxide synthase (nNOS), whereas those in the lateral wall did not. Distinct populations of SUCs were present in the bladder base. SUCs with significant amounts of nNOS lay adjacent to cells with low levels of nNOS. In specific base regions, the few SUCs present contained nNOS within discrete intracellular particles. In the basal urothelial cell (BUC) layer of the lateral wall, nNOS-positive (NOS(+)) BUCs neither showed an elevation in cGMP in response to NO, nor expressed the beta1 sub-unit of soluble guanylate cyclase, protein kinase I or protein kinase II. Thus, they produced but did not respond to NO. The BUC layer also stained for the stem cell factor c-Kit suggesting its involvement in urothelial cell development. No NOS(+) BUCs were present in the SUC-sparse region in the bladder base. Exogenous NO produced an elevation in cGMP in SUCs and SU-ICs. The distribution and proportion of these target cells varied between the dome, lateral wall and base. cGMP(+) SU-ICs were present as a dense layer in the bladder base but were rarely seen in the lateral wall, which contained nNOS(+) BUCs. No nNOS(+) BUCs and cGMP(+) SU-ICs were apparent in the dome. The degree of complexity in nNOS distribution and NO target cells is therefore greater than has previously been described and may reflect distinct physiological functions that have yet to be identified.
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PMID:Expression of neuronal nitric oxide synthase (nNOS) and nitric-oxide-induced changes in cGMP in the urothelial layer of the guinea pig bladder. 1596 54

Hormesis, a stress tolerance, can be induced by ischemic preconditioning stress. In addition to preconditioning, it may be induced by other means, such as gas anesthetics. Preconditioning mechanisms, which may be mediated by reprogramming survival genes and proteins, are obscure. A known neurotoxicant, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes less neurotoxicity in the mice that are preconditioned. Pharmacological evidences suggest that the signaling pathway of NO-cGMP-PKG (protein kinase G) may mediate preconditioning phenomenon. We developed a human SH-SY5Y cell model for investigating ()NO-mediated signaling pathway, gene regulation, and protein expression following a sublethal preconditioning stress caused by a brief 2-h serum deprivation. Preconditioned human SH-SY5Y cells are more resistant against severe oxidative stress and apoptosis caused by lethal serum deprivation and 1-methyl-4-phenylpyridinium (MPP(+)). Both sublethal and lethal oxidative stress caused by serum withdrawal increased neuronal nitric oxide synthase (nNOS/NOS1) expression and ()NO levels to a similar extent. In addition to free radical scavengers, inhibition of nNOS, guanylyl cyclase, and PKG blocks hormesis induced by preconditioning. S-nitrosothiols and 6-Br-cGMP produce a cytoprotection mimicking the action of preconditioning tolerance. There are two distinct cGMP-mediated survival pathways: (i) the up-regulation of a redox protein thioredoxin (Trx) for elevating mitochondrial levels of antioxidant protein Mn superoxide dismutase (MnSOD) and antiapoptotic protein Bcl-2, and (ii) the activation of mitochondrial ATP-sensitive potassium channels [K(ATP)]. Preconditioning induction of Trx increased tolerance against MPP(+), which was blocked by Trx mRNA antisense oligonucleotide and Trx reductase inhibitor. It is concluded that Trx plays a pivotal role in ()NO-dependent preconditioning hormesis against MPTP/MPP(+).
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PMID:Roles of thioredoxin in nitric oxide-dependent preconditioning-induced tolerance against MPTP neurotoxin. 1600 85

The ability of endothelins 1 and 3 (ET-1 and ET-3) to reduce neuronal norepinephrine release through ETB receptor activation involving nitric oxide (NO) pathways in the rat anterior hypothalamus region (AHR) was previously reported. In the present work, we studied the effects of ET-1 and -3 on tyrosine hydroxylase (TH) activity and the possible involvement of NO pathways. Results showed that ET-1 and -3 (10 nM) diminished TH activity in AHR and this effect was blocked by a selective ETB receptor antagonist (100 nM BQ-788), but not by a ET(A) receptor antagonist (BQ-610). To confirm these results, 1 microM IRL-1620 (ET(B) agonist) reduced TH activity whereas 300 nM sarafotoxin S6b falled to modify it. N(omega)-Nitro-L-arginine methyl ester (10 microM), 7-nitroindazole (10 microM), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-ona (10 microM), KT5823 (2 microM), inhibitors of nitric oxide synthase, neuronal nitric oxide synthase, NO-sensitive-guanylyl cyclase, and protein kinase G, respectively, did not modify the reduction of TH activity produced by ETs. In addition, both 100 microM sodium nitroprusside and 50 microM 8-bromoguanosine-3',5'-cyclic monophosphate (NO donor and guanosine-3',5'-cyclic monophosphate analog, respectively) diminished TH activity. Present results showed that ET-1 and ET-3 diminished TH activity through the activation of ET(B) receptors involving the NO/guanosine-3',5'-cyclic monophosphate/protein kinase G pathway. Taken jointly present and previous results it can be concluded that both ETs play an important role as modulators of norepinephrine neurotransmission in the rat AHR.
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PMID:Involvement of nitric oxide pathways in short term modulation of tyrosine hydroxylase activity by endothelins 1 and 3 in the rat anterior hypothalamus. 1602 17

Long-term depression (LTD) of the parallel fiber-Purkinje cell synapse in the cerebellum is a cellular model system that has been suggested to underlie certain forms of motor learning. Induction of cerebellar LTD requires a postsynaptic kinase limb involving activation of mGluR1, protein kinase Calpha (PKCalpha), and phosphorylation of ser-880 on the AMPA receptor subunit GluR2. Several lines of evidence have also implicated a complementary phosphatase limb in which N-methyl-d-aspartate (NMDA) receptor-mediated Ca(2+) influx activates neuronal nitric oxide synthase (nNOS), the ultimate consequences of which are mediated by nitric oxide (NO), cGMP, and inhibition of postsynaptic protein phosphatases. However, the cellular localization of an NMDA/NO cascade has been complicated by the fact that neither functional NMDA receptors nor nNOS are expressed in Purkinje cells. This has lead to a proposal in which NMDA receptors activate nNOS in parallel fibers. Here, we confirm that pharmacological blockade of NMDA receptor or NO signaling blocks induction of LTD. However, no evidence was found for functional NMDA receptors in parallel fiber terminals: blockade of NMDA receptors did not alter either presynaptic Ca(2+) transients or the frequency of miniature excitatory postsynaptic currents. NMDA receptor blockade did abolish a slow depolarization evoked by burst stimulation of parallel fiber-stellate cell synapses. The application of NMDA evoked a Ca(2+) transient in stellate cell terminals but not in parallel fiber terminals. These results are consistent with the hypothesis that an NMDA receptor/NO cascade involved in cerebellar LTD is localized to interneurons rather than parallel fibers.
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PMID:An NMDA receptor/nitric oxide cascade is involved in cerebellar LTD but is not localized to the parallel fiber terminal. 1612 Jun 58

Recently, a negative feedback effect of nitric oxide (NO) on the adenosine 5'-triphosphate (ATP)-induced Ca2+ response has been described in cochlear inner hair cells. We here investigated the role of NO on the ATP-induced Ca2+ response in outer hair cells (OHCs) of the guinea pig cochlea using the NO-sensitive dye DAF-2 and Ca2+ -sensitive dye fura-2. Extracellular ATP induced NO production in OHCs, which was inhibited by L-NG-nitroarginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor, and suramin, a P2 receptor antagonist. ATP failed to induce NO production in the Ca2+ -free solution. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, enhanced the ATP-induced increase of the intracellular Ca2+ concentrations ([Ca2+]i), while L-NAME inhibited it. SNAP accelerated ATP-induced Mn2+ quenching in fura-2 fluorescence, while L-NAME suppressed it. 8-Bromoguanosine-cGMP, a membrane permeable analog of cGMP, mimicked the effects of SNAP. 1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase inhibited the ATP-induced [Ca2+]i increase. Selective neuronal NOS inhibitors, namely either 7-nitro-indazole or 1-(2-trifluoromethylphenyl) imidazole, mimicked the effects of L-NAME regarding both ATP-induced Ca2+ response and NO production. Immunofluorescent staining of neuronal nitric oxide synthase (nNOS) in isolated OHCs showed the localization of nNOS in the apical region of OHCs. These results suggest that the ATP-induced Ca2+ influx via a direct action of P2X receptors may be the principal source for nNOS activity in the apical region of OHCs. Thereafter, NO can be produced while conversely enhancing the Ca2+ influx via the NO-cGMP-PKG pathway by a feedback mechanism.
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PMID:Role of nitric oxide on ATP-induced Ca2+ signaling in outer hair cells of the guinea pig cochlea. 1650 Jun 27

nNOS (neuronal nitric oxide synthase) is a constitutively expressed enzyme responsible for the production of NO* from L-arginine and O2. NO* acts as both an intra- and an inter-cellular messenger that mediates a variety of signalling pathways. Previous studies from our laboratory have demonstrated that nNOS production of NO* blocks Ca2+-ionophore-induced activation of ERK1/2 (extracellular-signal-regulated kinase 1/2) of the mitogen-activated protein kinases through a mechanism involving Ras G-proteins and Raf-1 kinase. Herein we describe a mechanism by which NO* blocks Ca2+-mediated ERK1/2 activity through direct modification of H-Ras. Ca2+-mediated ERK1/2 activation in NO*-producing cells could be restored by exogenous expression of constitutively active mitogen-activated protein kinase kinase 1. In contrast, exogenous expression of constitutively active mutants of Raf-1 and H-Ras only partially restored ERK1/2 activity, by 50% and 10% respectively. On the basis of these findings, we focused on NO*-mediated mechanisms of H-Ras inhibition. Assays for GTP loading and H-Ras interactions with the Ras-binding domain on Raf-1 demonstrated a decrease in H-Ras activity in the presence of NO*. We demonstrate that S-nitrosylation of H-Ras occurs in nNOS-expressing cells activated with Ca2+ ionophore. Mutation of a putative nitrosylation site at Cys118 inhibited S-nitrosylation and restored ERK1/2 activity by constitutively active H-Ras even in the presence of NO*. These findings indicate that intracellular generation of NO* by nNOS leads to S-nitrosylation of H-Ras, which interferes with Raf-1 activation and propagation of signalling through ERK1/2.
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PMID:Neuronal nitric oxide synthase-induced S-nitrosylation of H-Ras inhibits calcium ionophore-mediated extracellular-signal-regulated kinase activity. 1656 14

Dexras1 is a 30 kDa G protein in the Ras subfamily whose discovery was based on its pronounced inducibility by the glucocorticoid dexamethasone. It binds to neuronal nitric oxide synthase (nNOS) via the adaptor protein CAPON, eliciting S-nitrosylation and activation of Dexras1. We report that Dexras1 binds to the peripheral benzodiazepine receptor-associated protein (PAP7), a protein of unknown function that binds to cyclic AMP-dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 in turn binds to the divalent metal transporter (DMT1), an iron import channel. We have identified a signaling cascade in neurons whereby stimulation of NMDA receptors activates nNOS, leading to S-nitrosylation and activation of Dexras1, which, via PAP7 and DMT1, physiologically induces iron uptake. As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity.
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PMID:NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. 1690 9

We previously demonstrated that Ca2+/calmodulin (CaM)-dependent protein kinase IIalpha (CaM-KIIalpha) can phosphorylate neuronal nitric oxide synthase (nNOS) at Ser847 and attenuate NOS activity in neuronal cells. In the present study we focused on chronological alteration in levels and cellular location of nNOS, phosphorylated (p)-Ser847-nNOS (NP847), CaM-KII and p-Thr286-CaM-KIIalpha following spinal cord injury (SCI) in mice. Western blot analysis showed nNOS to be significantly phosphorylated at Ser847 from 3 h after SCI, peaking at 24 h and gradually decreasing thereafter, and CaM-KII to be colocalized with nNOS after SCI. Immunohistochemical analysis revealed that SCI causes an increase in both NP847 and p-Thr286-CaM-KIIalpha in the nucleus intermediolateralis. These findings suggest that SCI induces p-Thr286-CaM-KIIalpha, which phosphorylates the nNOS at Ser847 in the nucleus intermediolateralis where NO is thought to play a role as a neurotransmitter in autonomic preganglionic neurons. Thus, the NP847 signaling pathway might be involved in the autonomic failure which occurs immediately after SCI.
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PMID:Phosphorylation of neuronal nitric oxide synthase at Ser847 in the nucleus intermediolateralis after spinal cord injury in mice. 1725 65

We have examined the participation of a neuronal nitric oxide synthase (nNOS) signaling pathway in the elaboration of motor neuron dendrites during embryonic life. During chick embryogenesis, nNOS is expressed by interneurons that surround the motor neuron pools in the ventral horn. Pseudorabies virus tracing suggests that these cells, while juxtaposed to motor neurons are not synaptically connected to them. The downstream effectors, soluble guanylyl cyclase (sGC) and protein kinase G (PKG), are found in motor neurons as well as several other populations of spinal cord cells. To determine the functional significance of the nNOS/sGC/PKG signaling pathway, pharmacological inhibitors were applied to chick embryos and the effects on motor neuron dendrites monitored. Inhibition of nNOS activity led to a lasting reduction in the overall size and degree of branching of the dendritic tree. These alterations in dendritic architecture were also seen when the activity of sGC or PKG was blocked. Our results suggest that normal motor neuron dendrite elaboration depends, in part, on the activity-dependent generation of NO by ventral horn interneurons, which then activates sGC and PKG in motor neurons.
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PMID:Embryonic motor neuron dendrite growth is stunted by inhibition of nitric oxide-dependent activation of soluble guanylyl cyclase and protein kinase G. 1743 87

Spontaneously hypertensive rats (SHR) are characterized by impaired erectile function and overactivity of the procontractile RhoA/Rho-associated, coiled-coil-containing protein kinase (RhoA/ROCK) pathway, as compared with their normotensive counterpart, Wistar-Kyoto rats. By measuring the intracavernous pressure:mean arterial pressure (ICP:MAP) ratio after electrostimulation of the cavernous nerve, we confirmed these findings and showed that responsiveness to sildenafil (25 mg/kg by oral gavage) also is hampered in SHR. A 2-week treatment with atorvastatin (5 and 30 mg/kg) improved the sildenafil-induced ICP:MAP increase and normalized RhoA and ROCK2 overexpression in SHR corpora cavernosa (CC). Conversely, other genes, neuronal nitric oxide synthase (NOS), endothelial NOS, and phosphodiesterase 5, were unaffected. In human fetal smooth muscle cells derived from CC (hfPSMC), atorvastatin inhibited RhoA membrane translocation and ROCK activity, as well as RhoA-dependent biologic functions like cell migration and cell proliferation. Atorvastatin's effect on migration was rescued in a dose-dependent manner by geranylgeranyl pyrophosphate, suggesting the involvement of RhoA geranylgeranylation. In hfPSMC, atorvastatin decreased the expression of RhoA-dependent genes such as ROCK2, desmin, alpha-smooth muscle actin, SM22alpha, and myocardin. In contrast to atorvastatin, elocalcitol, a vitamin D analog that also interferes with RhoA activation in SHR bladder, was unable to restore penile responsiveness to sildenafil. In conclusion, atorvastatin, but not elocalcitol, ameliorates sildenafil-induced penile erections in SHR, likely by interfering with RhoA/ROCK signaling within the penis.
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PMID:Atorvastatin but not elocalcitol increases sildenafil responsiveness in spontaneously hypertensive rats by regulating the RhoA/ROCK pathway. 1769 3


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