Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Injection of capsaicin into the skin results in pain, primary heat and mechanical hyperalgesia, and secondary mechanical allodynia and hyperalgesia. Sensory receptors in the area of secondary mechanical allodynia and hyperalgesia are unaffected, and so the sensory changes must be due to central actions of the initial intense nociceptive discharge that follows the capsaicin injection. Central sensitization of the responses of spinothalamic tract neurons lasts several hours, but can be prevented by spinal cord administration of non-NMDA and NMDA glutamate receptor antagonists or NK1 substance P receptor antagonists. The long-lasting increase in excitability of spinothalamic tract cells depends on the activation of several second messenger cascades (PKC, PKA, and NO/PKG signal transduction pathways). The excitability change also depends on activation of calcium/calmodulin-dependent kinase II, which is consistent with the proposal that this central sensitization response is a form of long-term potentiation.
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PMID:Role of neurotransmitters in sensitization of pain responses. 1200 17

The human protein kinase X gene (PRKX) is a member of an ancient family of cAMP-dependent serine/threonine kinases here shown to be phylogenetically distinct from the classical PKA, PKB/Akt, PKC, SGK, and PKG gene families. Renal expression of the PRKX gene is developmentally regulated and restricted to the ureteric bud epithelium of the fetal metanephric kidney. Aberrant adult kidney expression of PRKX was found in autosomal dominant polycystic kidney disease. PRKX kinase expression markedly activated migration of cultured renal epithelial cells in the presence of cAMP; this effect was blocked by cell treatment with the PKA inhibitor H89 and was not observed in PKA-transfected cells. In addition, expression of PRKX kinase activated branching morphogenesis of Madin-Darby canine kidney cells in collagen gels even in the absence of cAMP and/or hepatocyte growth factor, an effect not seen with either PKA expression or expression of a mutant, kinase-inactivated PRKX. These results suggest that the PRKX kinase may regulate epithelial morphogenesis during mammalian kidney development. Because another member of the PRKX gene family (the Dictyostelium discoideum gene KAPC-DICDI) also plays a role in cellular migration, these studies suggest that regulation of morphogenesis may be a distinctive property of these genes that has been conserved in evolution that is not shared with PKA family genes.
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PMID:PRKX, a phylogenetically and functionally distinct cAMP-dependent protein kinase, activates renal epithelial cell migration and morphogenesis. 1208 74

Gap junction-mediated communication can modulate cell death in different tissues. In myocardium, gap junction communication is altered during ischemia, which contributes to the development of arrhythmias, but still allows synchronization of the onset of rigor contracture in the progression of injury. During reperfusion, gap junction communication allows cell-to-cell spread of hypercontracture and cell death. Since the intracellular signal transduction systems involved in modulation of gap junction-mediated communication are activated during ischemic preconditioning, the hypothesis can be raised that gap junctions are end-effectors of preconditioning contributing to its protective effect on cell death. This paper reviews the available information supporting this hypothesis. It has been shown that ischemic preconditioning may influence gap junction-mediated intercellular communication by activation of different kinases, including PKC and MAPK cascades, and by preservation of cGMP among other mechanisms. Connexin phosphorylation by PKC, p38/MAPK, and PKG, tends to reduce intercellular communication. This effect of ischemic preconditioning seems to have no relevant consequences during prolonged ischemia, and does not significantly modify the time course of either electrical uncoupling or the frequency or temporal distribution of ventricular arrhythmias during this period. However, any modification of gap junction communication during initial reperfusion could contribute to the reduced extent of hypercontracture and cell death observed in preconditioned hearts. The potential role of gap junctions as effectors of ischemic preconditioning against lethal injury secondary to ischemia-reperfusion deserves to be investigated in depth.
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PMID:Gap junction-mediated intercellular communication in ischemic preconditioning. 1216 Sep 42

We used amperometry to analyze the role of several second messengers and drugs in the exocytotic kinetics of bovine chromaffin cells. Activation of PKG produces a slowing down of exocytosis, which is not generally accompanied by changes in the net granule content of catecholamines. These effects are also observed after mild PKA activation. However, strong PKA stimulation also causes an increase in the apparent granule content of catecholamines, suggesting the presence of composed fusion. Conversely, PKC activation promotes acceleration of the exocytotic process. We also analyzed the contribution of different Ca(2+) channel subtypes to the exocytotic kinetics at the single event level. Although N-subtype channels do not contribute to total catecholamine release, their blockade produces a slowing down of exocytosis without changes in granule content. However, L or P/Q blockade causes, in addition, a reduction in the apparent granule content. The L-type agonist BAY-K-8644 produces giant secretory amperometric spikes, indicating that Ca(2+) favors composed fusion prior to exocytosis. Our data suggest that second messengers continuously regulate exocytotic kinetics and granule content. In addition, several well-known antihypertensive agents, such as sodium nitroprusside, organic nitrates, hydralazine, or Ca(2+) antagonists, could be acting through these novel mechanisms on sympathetic synapses by changing the synaptic performance, thereby producing additional vasodilatory effects.
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PMID:Pharmacological regulation of the late steps of exocytosis. 1243 18

Mitogenic cell proliferation requires a rapid and transient H2O2 generation, which is blocked by catalase or PKA activators. Previously, we observed that anemic HIV(+) individuals expressed acidic pIs of catalase in RBC with significantly high activities [Mol Cell Biochem 165: 77-81, 1996]. These findings led us to hypothesize that cell signaling molecules regulate catalase to control cell mitogenesis. To test the hypothesis, we determined (i) whether RBC counts correlate with their catalase activities, (ii) whether protein kinases and phosphatases alter catalase activity in vitro, and (iii) whether protein kinase activators increase catalase activity to suppress proliferation of cultured cells. The results indicated that RBC counts inversely correlated with RBC catalase activities in both HIV(+) (r: -0.6769, r2: 0.4582, n: 69 male, p < 0.0001) and HIV(-) (r: -0.3827, r2: 0.1464, n: 177 male, p < 0.0001) populations. Catalytic PKA, PKC and Casein Kinase II, but none of PKG, Ca2+/calmodulin kinase II and p34cdc/cyclinB, rapidly elevated catalase activity in vitro by up to 2-fold. Whereas a major CAT subunit (60 kDa) showed immunoreactive phosphoserine and phosphothreonine, the kinases- and gamma-32P-ATP-dependent phosphorylation occurred with a minor component (110 kDa). Among PKC isozymes examined, PKCzeta was the most effective modulator followed by PKCgamma, and protein phosphatase 1gamma and 2A decreased the catalase activity. PKA and PKCzeta activators of forskolin and okadaic acid increased catalase activity and 110 kDa expression in NIH3T3 cells up to 2.4-fold and suppressed the cell growth, showing an inverse correlation of the indices (r: -0.9286, r2: 0.8622, n: 18, p < 0.0001). Taken together, these results suggest for the first time that catalase is under the regulation of cell signaling molecules and capable of modulating mitogenic cell proliferation.
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PMID:Regulation of catalase enzyme activity by cell signaling molecules. 1248 79

A novel human testis-specific gene, NYD-SP12, was identified by hybridizing human adult or fetal testes cDNA samples with a human cDNA microarray containing 9216 clones. mRNA expression level of NYD-SP12 was 30-fold higher in human adult testes than fetal testes. Similarly, semi-quantitative RT-PCR revealed a differential expression pattern of an NYD-SP12 homologous gene in mouse adult and infant testes. PCR and hybridization analysis of NYD-SP12 mRNA from multiple human tissues indicated the expression of NYD-SP12 exclusively in the testis. In-situ hybridization revealed that the expression of this gene was confined to spermatogenic epithelium and was not found in interstitial cells. NYD-SP12 transcript was not detected in patients with spermatogenic arrest and Sertoli cell-only syndrome. NYD-SP12 cDNA (GenBank accession number: AF345909) consisted of 2070 bp. The predicted 1707 bp open-reading fragment encoded a 569 amino acid protein that was 77% identical to a mouse homologue. Furthermore, computerized SMART and Motif analysis revealed that the protein contained a Structural Classification Of Proteins (SCOP) domain in the C-terminus and a cluster of phosphorylation sites for PKC, CK and cAMP/cGMP-dependent protein kinase. Interestingly, the EGFP-NYD-SP12 fusion protein was localized to the Golgi apparatus. In conclusion, the results suggest that NYD-SP12 is involved in spermatogenesis, and that NYD-SP12-encoded protein might function in the Golgi apparatus.
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PMID:Identification and characterization of a novel human testis-specific Golgi protein, NYD-SP12. 1252 16

A reliable in vitro cytotoxic system is essential in neurocytotoxic and neuroprotective research. The present study examined four cytotoxic insults with the SK-N-SH human neuroblastoma cell line. These were beta-amyloid protein (Abeta), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), high density culture, and serum deprivation induced neuronal death. These insults induced significant reduction in cell numbers after 96 h culture, in a concentration dependent manner. Among all the insults, MPTP, serum deprivation, and high density culture induced apoptosis after 96 h, while Abeta presumably induced necrotic neuronal death since apoptosis was not detectable. The p38 MAP kinase inhibitor, SB203580 (1 microM), and the PKC inhibitor, chelerythrine (5 microM) successfully inhibited the loss in viability caused by Abeta and the high density culture, respectively. Other kinase inhibitors, including the non-specific protein kinase inhibitor, H7, the PKA inhibitor 14-22 Amide, the PKG inhibitor, KT5823, and the protein tyrosine kinase inhibitor, AG18 had no effect on any of the four cytotoxic models. This system allows the study of neuroprotection under conditions where the different pathways and mechanisms of the neurons can be considered within one cellular system, removing variations which may be due to different cell type studied. The present studies describe an effective model system for screening potential neuroprotective agents.
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PMID:The establishment of a reliable cytotoxic system with SK-N-SH neuroblastoma cell culture. 1258 45

Reabsorption of phosphate in the proximal tubule is mainly mediated by the type IIa Na(+)/P(i) cotransporter (NaPi-IIa) and tightly regulated by a variety of factors including dietary phosphate intake and parathyroid hormone (PTH). PTH signals through both apical and basolateral PTH receptors and induces the rapid internalization and subsequent degradation of NaPi-IIa. At least two signalling cascades can be activated by PTH: the PLC/PKC and the cAMP/PKA pathways. Recent evidence from OK cell culture suggested the involvement of MAPK kinases in the PTH action. Here we used freshly isolated coronal mouse kidney slices and incubated them in a physiological buffer in the absence and presence of PTH with inhibitors and activators of the various signalling cascades to further study the events leading to internalization of NaPi-IIa. No alterations in the pattern of immunostaining for alpha-tubulin, actin and several brush border membrane proteins demonstrated intactness of the slices over the experimental period. Application of PTH (100 nM) induced a strong decrease of NaPi-IIa brush border staining and internalization after 45 min of incubation. The localization of the Na(+)/sulphate cotransporter (NaSi), however, was not affected. The internalization of NaPi-IIa could be completely prevented by the PKC inhibitor chelerythrine (1 micro M) or the MAPK-kinase (ERK1/2) inhibitor PD098059 (20 micro M). Without PTH both inhibitors alone had no effect. PTH induced phosphorylation of the ERK1/2 MAPK-kinases which was prevented by PD 098059. Separate activation of the cAMP/PKA pathway by 8-Br-cAMP was completely prevented by PD098059 whereas activation of the PLC/PKC pathway by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) and the PKG pathway by 8-Br-cGMP induced internalization of NaPi-IIa which could be only partly blocked by PD 098059. Inhibition by SB203580 or activation by anisomycin of the p38 kinase pathway had no influence on NaPi-IIa localization under control conditions or after PTH stimulation. Furthermore, the PTH-induced decrease in NaPi-IIa protein could be reduced by PD 098059. These results suggest that the ERK1/2 MAPK kinase pathway plays a central role in the signalling of PTH leading to specific internalization and subsequent degradation of the type II NaPi-IIa cotransporter in the proximal tubule.
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PMID:Involvement of the MAPK-kinase pathway in the PTH-mediated regulation of the proximal tubule type IIa Na+/Pi cotransporter in mouse kidney. 1269 Apr 63

Hepatotoxicity of allyl alcohol involves its bioactivation to acrolein and subsequent protein sulfhydryl loss and lipid peroxidation. However, the links between these events and hepatocellular death are not known. The purpose of these studies was to examine whether specific signal transduction pathways are associated with allyl alcohol toxicity in hepatocytes. Inhibition or augmentation of cyclic AMP and/or protein kinase A (PKA) by Rp-Ado-3N,5N-cyclic monophosphorothioate triethylamine salt or 3-isobutyl-1-methylxanthine had no effect on allyl alcohol-induced cell death. H-7, an inhibitor of PKA, PKC, and PKG, partially inhibited cell killing by allyl alcohol, whereas chelerythrine chloride, a nonselective PKC inhibitor, almost completely abolished allyl alcohol cytotoxicity. Neither 2,2N,3,3N,4,4N-hexahydroxy-1,1N,-biphenyl-6,6N-dimethanol-dimethyl ether, a selective PKC alpha and beta inhibitor, nor bisindolylmaleimide I, an inhibitor of PKC alpha, beta, and epsilon, had any effect on allyl alcohol cytotoxicity. In contrast, rottlerin, a selective PKCdelta inhibitor, blocked hepatocellular killing by allyl alcohol. Cytoprotection by chelerythrine chloride and rottlerin was not the result of inhibition of bioactivation of allyl alcohol because each inhibitor also prevented cell death from acrolein. Western blotting and immunohistochemical techniques revealed that allyl alcohol stimulated phosphorylation and translocation of PKCdelta to hepatocyte membranes (i.e., activation), and this activity was inhibited by rottlerin. Cell death appeared to occur via oncotic necrosis rather than apoptosis based on single-stranded DNA ELISA and propidium iodide staining. Together, these results indicate that activation of PKCdelta is a critical, early event in initiating hepatocyte injury and death from allyl alcohol.
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PMID:Allyl alcohol activation of protein kinase C delta leads to cytotoxicity of rat hepatocytes. 1275 90

The slow EPSP (sEPSP) or slow EPSC (sEPSC) at parallel fiber to Purkinje neuron synapses is attributable to a nonselective cation channel coupled to activation of metabotropic type 1 glutamate receptors (mGluR1s). Photorelease of L-glutamate in 1 msec from 4-methoxy-7-nitroindolinyl-or 7-nitroindolinyl-caged glutamate in cerebellar slices was used to isolate and study postsynaptic mechanisms coupling mGluR1 to the cation channel. L-Glutamate immediately activated a glutamate transporter current, followed by the slow mGluR1-activated conductance. Inhibitors of kinases, phosphatases, and G-proteins were tested on the peak glutamate-evoked currents. No effects of the inhibitors were seen on the initial glutamate transporter currents. In contrast, the later mGluR1 currents were either unaffected or enhanced by the protein tyrosine kinase (PTK) inhibitors PP1, K252a, and staurosporine were diminished or blocked by phosphatase inhibitors but were unaffected by inhibitors of serine-threonine kinases PKA, PKC, or PKG. The selective src-PTK inhibitor PP1 (10 microm intracellularly) potentiated submaximal mGluR1 currents evoked by low L-glutamate concentrations but had no effect on maximal responses (80 or 160 microm L-glutamate). L-Glutamate-evoked mGluR1 currents and parallel fiber sEPSCs were reversibly and completely inhibited by protein tyrosine phosphatase (PTP) inhibitor bpV(phen) (50-200 microm) and by nonselective phosphatase inhibitor orthovanadate (0.5 or 1 mm). mGluR1 currents were completely inhibited by GDPbetaS applied intracellularly (5 mm). The results confirm a role for a GTPase postsynaptically, show that tyrosine phosphorylation inhibits mGluR1 coupling to the channel, and show that PTPs increase activation by tyrosine dephosphorylation most likely upstream of the sEPSP cation channel.
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PMID:Evidence for protein tyrosine phosphatase, tyrosine kinase, and G-protein regulation of the parallel fiber metabotropic slow EPSC of rat cerebellar Purkinje neurons. 1276 93


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