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)

Neuronal nitric-oxide synthase (nNOS) is a constitutively expressed enzyme responsible for the production of nitric oxide (NO*) from l-arginine and O2. Nitric oxide is an intra- and intercellular messenger that mediates a diversity of signaling pathways in target cells. In the absence of l-arginine, nNOS has been shown to generate superoxide (O2*). Superoxide, either directly or through its self-dismutation to H2O2, is likewise believed to be a cell-signaling agent. Because nNOS can generate NO* and O2*, we examined the activation of cellular signal transduction pathways in nNOS-transfected cells grown in the presence or absence of l-arginine. Spin trapping/EPR spectroscopy confirmed that stimulated nNOS-transfected cells grown in an l-arginine environment secreted NO* into the surrounding milieu. Production of NO* blocked Ca2+ ionophore-induced activation of the ERK1/2 through a mechanism involving inhibition of the Ras G-protein and Raf-1 kinase. In contrast, ERK activation was largely unaffected in nNOS-transfected cells grown in l-arginine-free media. Inhibition of nNOS-generated NO* with the competitive NOS inhibitor, NG-nitro-l-arginine methyl ester, in cells grown in l-arginine restored ERK1/2 activation to levels similar to that found when nNOS was activated in l-arginine-free media. These findings indicate that nNOS can differentially regulate the ERK signal transduction pathway in a manner dependent on the presence of l-arginine and the production of NO*.
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PMID:Nitric oxide inhibition of ERK1/2 activity in cells expressing neuronal nitric-oxide synthase. 1460 25

1. The mechanisms and receptors involved in the vasoactive intestinal peptide (VIP)- and pituitary adenylate cyclase-activating polypeptide (PACAP)-induced relaxations of the pig intravesical ureter were investigated. 2. VIP, PACAP 38 and PACAP 27 concentration-dependently relaxed U46619-contracted ureteral strips with a similar potency. [Ala(11,22,28)]-VIP, a VPAC(1) agonist, showed inconsistent relaxations. 3. The neuronal voltage-gated Ca(2+) channel inhibitor, omega-conotoxin GVIA (omega-CgTX, 1 microm), reduced the VIP relaxations. Urothelium removal or blockade of capsaicin-sensitive primary afferents, nitric oxide (NO) synthase and guanylate cyclase with capsaicin (10 microm), N(G)-nitro-l-arginine (l-NOARG, 100 microm) and 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 5 microm), respectively, did not change the VIP relaxations. However, the PACAP 38 relaxations were reduced by omega-CgTX, capsaicin, l-NOARG and ODQ. 4. The VIP and VIP/PACAP receptor antagonists, [Lys(1), Pro(2,5), Arg(3,4), Tyr(6)]-VIP (1 microm) and PACAP (6-38) (0.4 microm), inhibited VIP and VIP and PACAP 38, respectively, relaxations. 5. The nonselective and large-conductance Ca(2)-activated K(+) channel blockers, tetraethylammonium (3 mm) and charybdotoxin (0.1 microm), respectively, and neuropeptide Y (0.1 microm) did not modify the VIP relaxations. The small-conductance Ca(2)-activated K(+) channel blocker apamin (1 microm) did not change the PACAP 27 relaxations. 6. The cAMP-dependent protein kinase A (PKA) blocker, 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphorothioate (Rp-8-CPT-cAMPS, 100 microm), reduced VIP relaxations. The phosphodiesterase 4 inhibitor rolipram and the adenylate cyclase activator forskolin relaxed ureteral preparations. The rolipram relaxations were reduced by Rp-8-CPT-cAMPS. Forskolin (30 nm) evoked a potentiation of VIP relaxations. 7. These results suggest that VIP and PACAP relax the pig ureter through smooth muscle receptors, probably of the VPAC(2) subtype, linked to a cAMP-PKA pathway. Neuronal VPAC receptors localized at motor nerves and PAC(1) receptors placed at sensory nerves and coupled to NO release, seem also to be involved in the VIP and PACAP 38 relaxations.
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PMID:Heterogeneity of neuronal and smooth muscle receptors involved in the VIP- and PACAP-induced relaxations of the pig intravesical ureter. 1466 37

Neuronal responses to alcohol involve several hormone- and neurotransmitter-activated signal transduction pathways. Recent studies suggest that the adenosine A2 receptor (A2) mediates important actions of alcohol. Ethanol inhibits adenosine reuptake, increases extracellular adenosine, and promotes activation of A2. This leads to enhanced cAMP/protein kinase A (PKA) signaling ranging from increases in cAMP to stimulation of cAMP-dependent cAMP response element (CRE)-mediated gene expression. Medium spiny neurons in the striatum/nucleus accumbens (NAc) express A2 and dopamine D2 receptor (D2) on the same cells. Studies in model neuronal cell lines and primary neurons in culture expressing A2 and D2 provide evidence for synergy between ethanol/A2 and D2. Subthreshold concentrations of ethanol or a D2 agonist, without effect separately, synergistically activate cAMP/PKA signaling. Thus, neurons expressing A2 and D2 on the same cells, like in the NAc, are characterized by hypersensitivity to ethanol with a simultaneous activation of dopaminergic signaling. Synergy requires adenosine and appears to be mediated by the release of free betagamma dimers from G(i/o) via D2 activation. The release of free betagamma has pathophysiological significance in the drinking animal because specific blockade of betagamma signaling in the NAc strikingly reduces voluntary alcohol consumption. These findings suggest that signaling pathways, which regulate synergy between A2 and D2, might contain molecular targets for the prevention and treatment of alcoholism and alcohol abuse.
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PMID:Recent advances in the neurobiology of alcoholism: the role of adenosine. 1472 91

Based upon the existence of high density of ET-receptors on catecholaminergic neurons of the hypothalamus, we studied the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on neuronal norepinephrine (NE) release in the rat posterior hypothalamus. The intracellular pathways and receptors involved were also investigated. Neuronal NE release was enhanced by ET-1 and ET-3 (10 etaM). The selective antagonists of subtype A and B ET receptors (ETA, ETB) (100 etaM BQ-610 and 100 etaM BQ-788, respectively) abolished the increase induced by ET-1 but not by ET-3. The PLC inhibitor, U73122 (10 microM), abolished ET-1 and ET-3 response. GF-109203X (100 etaM) (PKC inhibitor) blocked the increase in NE release produced by ET-3 and partially blocked ET-1 response. The inositol 1,4,5-trisphosphate-induced calcium release inhibitor, 42 microM 2-APB, inhibited the stimulatory effect induced by ET-3 but not by ET-1. The PKA inhibitor, 500 etaM H-89, blocked the increase in neuronal NE release evoked by ET-1 but not by ET-3. Our results showed that ET-1 as well as ET-3 displayed an excitatory neuromodulatory effect on neuronal NE release in the rat posterior hypothalamus. ET-1 through an atypical ETA or ETB receptor activated the PLC/PKC signalling pathway as well as the cAMP pathway, whereas ET-3 through a non-ETA/non-ETB receptor activated the phosphoinositide pathway. Both ETs would enhance the sympathoexcitatory response elicited by the posterior hypothalamus and thus participate in cardiovascular regulation.
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PMID:Modulatory effect of endothelin-1 and -3 on neuronal norepinephrine release in the rat posterior hypothalamus. 1475 57

Neuronal excitability has a large impact on network behavior, and plasticity in intrinsic excitability could serve as an important information storage mechanism. Here we ask whether postsynaptic excitability of layer V pyramidal neurons from primary visual cortex can be rapidly regulated by activity. Whole cell current-clamp recordings were obtained from visual cortical slices, and intrinsic excitability was measured by recording the firing response to small depolarizing test pulses. Inducing neurons to fire at high-frequency (30-40 Hz) in bursts for 5 min in the presence of synaptic blockers increased the firing rate evoked by the test pulse. This long-term potentiation of intrinsic excitability (LTP-IE) lasted for as long as we held the recording (>60 min). LTP-IE was accompanied by a leftward shift in the entire frequency versus current (F-I) curve and a decrease in threshold current and voltage. Passive neuronal properties were unaffected by the induction protocol, indicating that LTP-IE occurred through modification in voltage-gated conductances. Reducing extracellular calcium during the induction protocol, or buffering intracellular calcium with bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid, prevented LTP-IE. Finally, blocking protein kinase A (PKA) activation prevented, whereas pharmacological activation of PKA both mimicked and occluded, LTP-IE. This suggests that LTP-IE occurs through postsynaptic calcium influx and subsequent activation of PKA. Activity-dependent plasticity in intrinsic excitability could greatly expand the computational power of individual neurons.
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PMID:Long-term potentiation of intrinsic excitability in LV visual cortical neurons. 1497 17

Inositol 1,4,5-trisphosphate receptors (InsP(3)R) play a key role in intracellular calcium (Ca(2+)) signaling. Three InsP(3)R isoforms are expressed in mammals. Type 1 InsP(3)R (InsP(3)R1) is a predominant neuronal isoform. Neuronal InsP(3)R1 is one of the major substrates of protein kinase A (PKA) phosphorylation. In our previous study (Tang, T. S., Tu, H., Wang, Z., and Bezprozvanny, I. (2003) J. Neurosci. 23, 403-415) we discovered a direct association between InsP(3)R1 and protein phosphatase 1 alpha (PP1 alpha). In functional experiments we demonstrated that phosphorylation by PKA activates InsP(3)R1 and that dephosphorylation by PP1 alpha inhibits InsP(3)R1. To extend these findings, here we investigated the possibility of InsP(3)R1-PKA association. In a series of biochemical experiments we demonstrate the following findings. 1) InsP(3)R1 and PKA associate in the brain. 2) InsP(3)R1-PKA association is mediated by the AKAP9 (Yotiao) multi-functional PKA anchoring protein. 3) InsP(3)R1-AKAP9 association is mediated via the leucine/isoleucine zipper (LIZ) motif in the InsP(3)R1 coupling domain and the fourth LIZ motif in AKAP9. 4) The InsP(3)R association with AKAP9 is specific for type 1 InsP(3)R. 5) Both the SII(+) and the SII(-) coupling domain splice variants of InsP(3)R1 bind to AKAP9. 6) Binding to AKAP9 promotes association of neuronal InsP(3)R1 with the NR1 NMDA receptor; and 7) neuronal InsP(3)R1 associate with PP1 directly via carboxy-terminus and indirectly via AKAP9. The obtained results advance our understanding of cross-talk between cAMP and InsP(3)/Ca(2+) signaling pathways in the brain.
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PMID:Association of type 1 inositol 1,4,5-trisphosphate receptor with AKAP9 (Yotiao) and protein kinase A. 1498 33

Neurotrophins such as nerve growth factor (NGF) are considered putative neuroprotective compounds in the central nervous system. To investigate the cellular and molecular neuroprotective mechanisms of NGF under ischemia, we used a unique oxygen and glucose deprivation (OGD) device. In this system we used pheochromocytoma PC12 cells to elucidate NGF neuroprotective effect. PC12 cells were exposed to OGD, followed by addition of glucose and oxygen (OGD reperfusion). Neuronal cell death induced in this model was measured by the release of lactate dehydrogenase (LDH), activation of caspase-3 and mitogen-activated protein kinases (MAPKs), measured with specific anti-phospho-antibodies. Pretreatment of the cultures with 50 ng/mL NGF, 18 h prior to OGD insult, conferred 30% neuroprotection. However, treatment of the cultures with NGF concomitantly with the OGD insult did not result in neuroprotection. Time-course experiments showed marked activation of extracellular signal-regulated protein kinase, c-Jun N-terminal kinase (JNK), and p38 MAPK isoforms during the OGD phase but not during OGD reperfusion. Pretreatment of the cultures with 50 ng/mL NGF, 18 h prior to OGD insult, resulted in 50% attenuation of OGD-induced activation of JNK1, and 20% and 50% attenuation of OGD-induced activation of p38alpha and beta, respectively. These findings support the notion that NGF confers neuroprotection from OGD insult, a phenomenon coincidentally related to differential inhibition of MAPK stress kinase isoforms, and provide the PC12 model as an in vitro OGD system to investigate molecular mechanisms of neurotoxicity and neuroprotection.
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PMID:Nerve growth factor pretreatment attenuates oxygen and glucose deprivation-induced c-Jun amino-terminal kinase 1 and stress-activated kinases p38alpha and p38beta activation and confers neuroprotection in the pheochromocytoma PC12 Model. 1499 18

Neuronal transmission of information requires polarized distribution of membrane proteins within axonal compartments. Membrane proteins are synthesized and packaged in membrane-bounded organelles (MBOs) in neuronal cell bodies and later transported to axons by microtubule-dependent motor proteins. Molecular mechanisms underlying targeted delivery of MBOs to discrete axonal subdomains (i.e. nodes of Ranvier or presynaptic terminals) are poorly understood, but regulatory pathways for microtubule motors may be an essential step. In this work, pharmacological, biochemical and in vivo experiments define a novel regulatory pathway for kinesin-driven motility in axons. This pathway involves enzymatic activities of cyclin-dependent kinase 5 (CDK5), protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK3). Inhibition of CDK5 activity in axons leads to activation of GSK3 by PP1, phosphorylation of kinesin light chains by GSK3 and detachment of kinesin from transported cargoes. We propose that regulating the activity and localization of components in this pathway allows nerve cells to target organelle delivery to specific subcellular compartments. Implications of these findings for pathogenesis of neurodegenerative diseases such as Alzheimer's disease are discussed.
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PMID:A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. 1515 89

Postganglionic parasympathetic neurons in guinea-pig cardiac ganglia exhibit choline acetyltransferase (ChAT)-immunoreactivity, and a large fraction (60%) of the ChAT-positive cardiac neurons co-express somatostatin-immunoreactivity. This co-expression remained when the cardiac ganglia explants were maintained in culture for 72 h (40% somatostatin-immunoreactive). The guinea-pig cardiac ganglia neurons express the high affinity pituitary adenylate cyclase activating polypeptide (PACAP)-selective PAC1 receptor, and treatment of the ganglia explants with 20 nM PACAP27 for 72 h to evaluate PACAP regulation of somatostatin expression revealed a dramatic 85% decrease in the number of somatostatin-IR neurons (6% somatostatin-IR neurons) compared with untreated control explant preparations. The decrease in percentage of somatostatin-IR neurons by PACAP27 was time- and concentration-dependent, and selective for PACAP27; PACAP38 and vasoactive intestinal polypeptide were less effective. PACAP6-38, a PACAP antagonist, eliminated the PACAP27-induced change in somatostatin positive neurons. The PACAP-mediated decrease in somatostatin-IR neurons was eliminated in calcium-deficient solutions and by the addition of nifedipine, indicating a requirement for calcium influx through L-type calcium channels. The addition of either the calmodulin inhibitor N-(4-aminobutyl)-1-naphthalenesulfonamide or the MEK inhibitor PD98059, also eliminated the PACAP27-induced decrease in somatostatin-IR cells. The PACAP27-mediated effect on somatostatin expression was not affected by inhibitors of protein kinase A or phospholipase C, but was reduced by the adenylyl cyclase inhibitor SQ22356, suggesting cAMP involvement. Semiquantitative and quantitative reverse transcription PCR prosomatostatin transcript measurements showed that cardiac ganglia prosomatostatin mRNA levels were not diminished by chronic PACAP27 exposure despite the dramatic decrement in somatostatin-expressing neurons. Neuronal peptide-IR content represents a balance between production and secretion. These results suggested that one of the primary effects of PACAP exposure may be enhanced levels of neuropeptide release that exceeded production levels, resulting in somatostatin depletion and a decrement in the number of identifiable somatostatin-expressing cardiac neurons.
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PMID:Pituitary adenylate cyclase activating polypeptide (PACAP) decreases neuronal somatostatin immunoreactivity in cultured guinea-pig parasympathetic cardiac ganglia. 1520 51

Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (p-Erk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3beta and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.
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PMID:Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. 1532 21


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