Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unbridled increases in intracellular ionized calcium can result in neuronal damage and death. Since many of the deleterious effects of calcium are mediated by calmodulin, we have sought to identify neuronal proteins that inhibit activation of this ubiquitous protein. PEP-19 is a 7.6-kDa neuron-specific protein, which contains a motif similar to the calmodulin binding domains of neuromodulin (GAP-43) and neurogranin (RC3). Here we show that PEP-19 binds calmodulin in an analogous calcium-independent manner with an apparent Kd near 1.2 microM. Furthermore, using the calmodulin-dependent enzyme neuronal nitric oxide synthase, we demonstrate that native PEP-19 is also an antagonist of enzyme activity. Based on the PEP-19 sequence, a series of peptide calmodulin antagonists termed camstatins were synthesized. These analogs define the minimally active domain of PEP-19 and provide a structure/activity relationship for calmodulin antagonism. There was a positive correlation between the binding affinities of the camstatins for calmodulin and their potencies as neuronal nitric oxide synthase inhibitors. Despite the similar IQ motif in PEP-19 and neuromodulin or neurogranin, PEP-19 was not a substrate for protein kinase C. The properties of PEP-19 suggest that it could fulfill a role in neuroprotection.
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PMID:Camstatins are peptide antagonists of calmodulin based upon a conserved structural motif in PEP-19, neurogranin, and neuromodulin. 866 25

The effects on neuronal nitric oxide synthase (NOS) of protein kinase C (PKC) activation in rat cerebellar slices and of in vitro phosphorylation by PKC were compared. Incubation of slices with 1-aminocyclopentane-1,3-trans-dicarboxylic acid (trans-ACPD) or phorbol myristate acetate (PMA) in the presence of okadaic acid (OA) shifted the calcium sensitivity of neuronal NOS in the homogenate or in the cytosolic fraction. trans-ACPD promoted translocation of PKC activity to the particulate fraction in the slices. PMA in the presence of OA enhanced phosphorylation of GAP43 protein in the slices. These results ensured that both treatments activated PKC in the slice. However, when neuronal NOS in the slice treated with PMA and OA, in which GAP43 phosphorylation was detected, was immunoprecipitated by a specific antibody, no indication of neuronal NOS phosphorylation was obtained. Nevertheless, PKC phosphorylated partially purified neuronal NOS in vitro. Phosphorylated neuronal NOS showed greater activity than unphosphorylated NOS, but their calcium sensitivity was identical. These data indicated that neuronal NOS is not susceptible to PKC-dependent phosphorylation in cerebellar slices and that the calcium-sensitivity shift of neuronal NOS takes place without direct phosphorylation of neuronal NOS, suggesting the involvement of unknown proteins whose phosphorylation would regulate the calcium sensitivity of neuronal NOS in the cerebellum.
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PMID:Differential effects of protein kinase C on neuronal nitric oxide synthase activity in rat cerebellar slices and in vitro. 881 26

Calpain (calcium-activated neutral protease) has been implicated as playing a role of neuronal injury in cerebral ischemia and excitotoxicity. Here we report that, in addition to extreme excitotoxic conditions [N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate challenges], other neurotoxins such as maitotoxin, A23187, and okadaic acid also induce calpain activation, as detected by m-calpain autolytic fragmentation and nonerythroid alpha-spectrin breakdown. Under the same conditions, calmodulin-dependent protein kinase II-alpha (CaMPK-IIalpha) and neuronal nitric oxide synthase (nNOS) are both proteolytically cleaved by calpain. Such fragmentation can be reduced by calpain inhibitors (acetyl-Leu-Leu-Nle-CHO and PD151746). In vitro digestion of protein extract from cortical cultures with purified mu- and m-calpain produced fragmentation patterns for CaMPK-IIalpha and nNOS similar to those produced in situ. Also, several other calpain-sensitive calmodulin-binding proteins (plasma membrane calcium pump, microtubule-associated protein 2, and calcineurin A) and protein kinase C-alpha are also degraded in neurotoxin-treated cultures. Lastly, in a rat pup model of acute excitotoxicity, intrastriatal injection of NMDA resulted in breakdown of CaMPK-IIalpha and nNOS. The degradation of CaMPK-IIalpha, nNOS, and other endogenous calpain substrates may contribute to the neuronal injury associated with various neurotoxins.
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PMID:Neuronal nitric oxide synthase and calmodulin-dependent protein kinase IIalpha undergo neurotoxin-induced proteolysis. 928 22

Changes in the regional distribution of protein kinase C (PKC) after transient focal cerebral ischemia in SV-129 mice were assessed by quantitative autoradiography using [3H]phorbol-12,13-dibutyrate ([3H]PDBu) binding. [3H]PDBu binding did not change up to 10 min after reperfusion of 3 h ischemia, but at 1 h after reperfusion markedly decreased to 40-50% of control (pre-ischemia) in the ipsilateral striatum and the middle cerebral artery (MCA) region of cortex in SV-129 mice. The binding decreased to 20% of control at 3-7 days after reperfusion, but did not change in the ipsilateral anterior cerebral artery (ACA) territory or the contralateral brain. In the ipsilateral substantia nigra, which lies outside the ischemic zone, [3H]PDBu binding was not significantly changed compared to the control values (pre-ischemia) at early phase (up to 3 h after reperfusion), but marked reduction of the binding was observed 1 day after reperfusion. After 3 h ischemia followed by 3 h reperfusion, the morphological damage and the decrease in [3H]PDBu binding in the ipsilateral striatum and the MCA region of cortex was smaller in mice lacking the expression of neuronal nitric oxide synthase (type I NOS) gene mutant mice compared to wild-type (SV-129 and C57black/6) mice. Our data suggest that postischemic alterations of PKC binding activity were observed in the ischemic and non-ischemic lesions in the mouse brain.
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PMID:Alteration of protein kinase C activity after transient focal cerebral ischemia in mice using in vitro [3H]phorbol-12,13-dibutyrate binding autoradiography. 945 94

Binding of (6R)-5,6,7,8-tetrahydro-L-biopterin (H4B) stabilizes the homodimeric structure of neuronal nitric oxide synthase (nNOS). In the present study, low-temperature sodium dodecylsulfate-polyacrylamide gel electrophoresis revealed differential susceptibility of stabilized and non-stabilized dimers to in vitro phosphorylation by protein kinase C. Protein kinase C preferentially phosphorylated the non-stabilized dimer. Although a low extent of phosphorylation was detected in the stabilized dimer, most of it was estimated to be due to phosphorylation of the dimer before its stabilization. Phosphorylation did not affect the stabilizing effect of H4B. These results indicate that H4B-dependent dimer stabilization prevents nNOS from protein kinase C-dependent phosphorylation in vitro.
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PMID:Tetrahydrobiopterin-dependent stabilization of neuronal nitric oxide synthase dimer reduces susceptibility to phosphorylation by protein kinase C in vitro. 974 35

Endothelins, localized in the enteric nervous system, may play important roles in the morphogenesis of the gastrointestinal (GI) tract and in the regulation of GI motility. However, the role of endothelins in the GI sphincters, including the internal anal sphincter (IAS) have not been examined. We examined the actions of endothelins on the basal tone of the opossum IAS circular smooth muscle strips before and after different neurohumoral antagonists or inhibitors. Endothelins 1 and 2 produced a concentration-dependent biphasic effect on the basal tone of the IAS, an initial brief fall followed by a sustained rise. The fall in the IAS smooth muscle tone was not modified by atropine, guanethidine, or tetrodotoxin but was significantly attenuated by the nitric oxide synthase inhibitor L-NNA, the specific neuronal nitric oxide synthase inhibitor, 1-(2-trifluoromethylphenyl)imidazole, the N-type neuronal Ca++-channel blocker omega-conotoxin GVIA, and by the calmodulin antagonist W-13. Endothelin-induced contraction of the IAS, on the other hand, was not affected by any of the neurohumoral antagonists but was significantly inhibited by the selective protein kinase C inhibitor H-7 or the calmodulin inhibitor W-13. The combination of H-7 and W-13 had no additive effect in attenuating the contractile action of endothelin 1. There was clear evidence of a cross-tachyphylaxis to the actions of endothelin 1 and endothelin 2. We conclude that the endothelins exert important neuromodulatory effects on the basal tone of the IAS. The contractile action occurs directly at the smooth muscle and the relaxant action by the activation of neuronal nitric oxide synthase at the nerve terminals. The contraction and relaxation of the smooth muscle caused by endothelins 1 and 2 may involve distinct receptors that are similar for both endothelins. The excitatory actions of endothelin 1 involve both the protein kinase C and the Ca++-calmodulin pathways that may lie in series.
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PMID:Mechanisms and sites of action of endothelins 1 and 2 on the opossum internal anal sphincter smooth muscle tone in vitro. 986 76

Ethanol alone had no effect on neuronal nitric oxide synthase (nNOS) expression in PC12 cells. However, in the presence of nerve growth factor (NGF), nNOS expression was amplified (threefold, P < 0.05), compared to NGF alone. This increase was eliminated with pretreatment of PC12 cells with staurosporine, suggesting that the effects of ethanol on nNOS expression are mediated by a protein kinase C-dependent pathway.
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PMID:The synergistic action of ethanol and nerve growth factor in the induction of neuronal nitric oxide synthase. 1045 78

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), two members of the VIP/secretin/glucagon family, modulate neurotransmission via stimulation of protein kinases including cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the central and peripheral nervous systems. They are reported to co-exist with nitric oxide synthases (NOSs) and other neuropeptides within the nervous system and peripheral tissues. In the present study, we investigated the neuronal role of these peptides in NO production in PC12 cells. We showed that PACAP decreased NO production in a dose-dependent manner, and the activators of protein kinase A and C also inhibited the NO production in PC12 cells. RT-PCR experiments demonstrated that PC12 cells constitutively express the mRNAs for neuronal NOS and the PACAP-specific (PAC1) receptor, and we concluded that PACAP plays an important role in the regulation of nNOS activity through PAC1 receptor in PC12 cells.
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PMID:Pituitary adenylate cyclase activating polypeptide regulates the basal production of nitric oxide in PC12 cells. 1203 89

In this paper we have determined the different signaling pathways involved in M(1) muscarinic acetylcholine receptor (mAChR)-dependent stimulation of m1 mAChRs, neural and inducible isoforms of nitric oxide synthase (nNOS and iNOS)-mRNA gene expression of rat frontal cortex. Carbachol-stimulation of M(1) mAChRs exerts an increase in m1 mAChR-mRNA, activation of phosphoinositide (PI) turnover, translocation of protein kinase C (PKC) and stimulation of NOS activity. Inhibitors of phospholipase C (PLC), calcium/calmodulin and NOS, but not guanylate cyclase, prevent the carbachol-dependent increase of m1 mAChR-mRNA levels. These inhibitors also attenuate the muscarinic receptor-dependent increase in nNOS and iNOS mRNA levels. These results suggest that carbachol-activation of M(1) mAChRs increases m1 mAChR, nNOS and iNOS mRNA levels associated with increased production of nitric oxide (NO). The mechanism appears to occur secondarily to stimulation of PI turnover via PLC activation. This in turn, triggers a cascade reaction involving calcium/calmodulin and PKC, leading to activation of NOS. On the basis of our results, the activation of M(1) mAChRs appears to induce nNOS and iNOS expression and, reciprocally, the activator of NOS up-regulates m1 mAChR gene expression. These results may contribute to a better understanding of the effects and side effects of cholinomimetic treatment in patients with neurodegenerative diseases.
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PMID:Novel insight into the mechanisms involved in the regulation of the m1 muscarinic receptor, iNOS and nNOS mRNA levels. 1284 32

Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKCbeta inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKCbeta-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKCbeta and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.
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PMID:Protein kinase Cbeta selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons. 1288 29


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