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)

Neuronal tissue-specific proteins B-50 (GAP-43, neuromodulin) and neurogranin are phosphorylated by phosphorylase kinase with stoichiometries of 0.4 and 0.5 mol of phosphate/mol of protein, respectively. The apparent Km and kcat values determined at pH 8.2 for neurogranin phosphorylation are 28.4 microM and 139.3 min-1, respectively, and for B-50 phosphorylation are 22.8 microM and 33.2 min-1, respectively. As a substrate of phosphorylase kinase, phosphorylase is approximately 44 and approximately 13 times better than B-50 and neurogranin, respectively. Both proteins are better substrates of protein kinase C than of phosphorylase kinase and are phosphorylated on a single site by phosphorylase kinase. The sequence analyses of tryptic phosphopeptides isolated from neurogranin and B-50 phosphorylated by phosphorylase kinase revealed the same amino acid sequence, IQASF, indicating that phosphorylase kinase phosphorylates the calmodulin-binding regulatory regions of B-50 and neurogranin previously known to be phosphorylated by protein kinase C (Coggins, P. J., and Zwiers, H. (1989) J. Neurochem. 53, 1895-1901; Baudier, J., Deloulme, J. C., Dorsselaer, A. V., Black, D., and Matthes, W. D. (1991) J. Biol. Chem. 266, 229-237). In rat brain synaptosomes, a relatively high phosphorylase kinase specific activity is detected, and approximately 32% activity is associated with synaptic membranes where B-50 is localized. In rat brain homogenate and synaptosomal membranes, phosphorylation of a protein that co-migrates with B-50 on SDS-polyacrylamide gel electrophoresis is enhanced in the presence of exogenous phosphorylase kinase.
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PMID:Phosphorylase kinase phosphorylates the calmodulin-binding regulatory regions of neuronal tissue-specific proteins B-50 (GAP-43) and neurogranin. 845 96

Neuronal plasticity is a key issue in neuroscience. It is defined as the capability of the neuron to adapt to a changing internal or external environment, to previous experience or to trauma. It appears that during all phases of the individual life span in the nervous system, changes take place that relate to development, degeneration, and regeneration. Growth cones are a focus of neuronal plasticity, and current views emphasize the importance of local intracellular [Ca2+] to the control of their function. Hence, outgrowth of neurites from neurons in culture may be manipulated by drugs that affect intracellular Ca2+ homeostasis. In the adult nervous system, much research deals with synaptic plasticity, especially with the activity-dependent changes seen after long-term potentation of hippocampal synapses. As in the growth cone, such changes involve Ca(2+)-dependent pre- and postsynaptic processes, among which is the activation of protein kinase C. During aging, Ca2+ homeostasis may be slightly disturbed over a long period of time that could result in loss of function seen after a short, toxic high level of intracellular [Ca2+]. In this respect, the beneficial effects of chronic treatment with the L-channel Ca(2+)-blocker nimodipine on sensorimotor function of aged rats is discussed.
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PMID:Neuronal plasticity and function. 851 3

Neuronal factors co-released with neurotransmitters may play an important role in synaptic development and function. Extracellular application of adenosine 5'-triphosphate (ATP), a substance co-stored and co-released with acetylcholine (ACh) in peripheral nervous systems, potentiated the spontaneous secretion of ACh at developing neuromuscular synapses in Xenopus 1-day-old cell cultures, as shown by a marked increase in the frequency of spontaneous synaptic currents recorded in the post-synaptic muscle cell. ATP also increased the frequency of miniature endplate potentials in the isolated tails of 2-week-old Xenopus tadpoles, with much smaller effect than that observed in cell cultures. The potentiation effect of ATP on ACh release in Xenopus cell cultures was inhibited by L-type Ca2+ channel blockers, suggesting that the L-type Ca2+ channel is responsible for the positive regulation of spontaneous ACh secretion by ATP at the developing neuromuscular synapses. The frequency of spontaneous synaptic events was found to vary greatly from cell to cell in the culture, over two orders of magnitude. Synapses with high frequency events are probably under the influence of endogenously released ATP. In addition, ATP was shown to potentiate the responses of isolated myocytes to iontophoretically-applied ACh. Local application of ATP to one region of the elongated myocyte surface resulted in potentiated ACh responses only at the ATP-treated region. Single channel recording showed that ATP specifically increased the open time and opening frequency of embryonic-type, low conductance ACh channels. Pharmacological experiments suggest that ATP exerted both its pre- and post-synaptic effects by binding to P2-purinoceptors and activating protein kinase C. Moreover, the potentiation effects of ATP were restricted to the early stages of embryos. Taken together, these results suggest that ATP co-released with ACh or released from stimulated myocytes may promote synaptic development by potentiating pre-synaptic ACh release and post-synaptic ACh channel activity during the early phase of synaptogenesis.
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PMID:Regulatory role of ATP at developing neuromuscular junctions. 857 Aug 52

Brain angiotensin II (Ang II) plays a key role in blood pressure control in part by interacting with catecholamines (CA) and by stimulation of sympathetic pathways. The significance of Ang-CA interaction is further heightened by the presence of a hyperactive brain Ang II system in spontaneously hypertensive (SH) rat, a genetic model for essential hypertension. Neuronal cells in primary culture from the hypothalamus-brainstem that mimic in vivo situations in so far as many cellular actions of Ang II are concerned, have been used in the present study to elucidate Ang II regulation of CA by determining its cellular action on the norepinephrine transporter (NET) system. Ang II causes both acute and chronic stimulation of [3H]-norepinephrine (NE) uptake in neuronal cultures of Wistar Kyoto (WKY) rat brain. Acute stimulation begins as early as 5 min, reaches maximal levels in about 30 min in the presence of 100 nM Ang II, and is blocked by losartan, a specific antagonist for AT1 receptor subtype. In addition, this acute stimulation appears to be a posttranscriptional event and does not involve protein kinase C (PKC) or NET gene transcription. Chronic stimulation of [3H]-NE uptake by Ang II persists throughout the duration of Ang II incubation (24 h), is dose dependent, and is also mediated by AT1 receptor subtype. However, chronic stimulation of [3H]-NE uptake involves PKC, cfos, and NET gene transcription. Ang II also stimulates [3H]-NE uptake in neuronal cultures of SH rat brain, both acutely and chronically, by mechanisms similar to those observed in neuronal cultures of WKY rat brain. The stimulation of NET by Ang II is 2-fold higher than that seen in WKY and is consistent with increased AT1 receptor gene transcription and increased functional AT1 receptors in SH rat brain neurons compared with WKY rat brain neurons. The Ang II stimulation of the NET system is also higher in adult SH compared with WKY rats in vivo. These observations show that 1) Ang II stimulates the NET system both acutely and chronically, the former involving activation of preexisting transporters and the latter involving NET gene transcription and translation; and 2) Ang II stimulation of the NET system is elevated in SH rat brain neurons.
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PMID:Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. 859 28

Neuronal cells in primary culture from the hypothalamus-brain stem areas of normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains have been used in the present study to investigate an interaction between the brain renin-angiotensin II system and the plasminogen activator system. This is an attempt to further our understanding of the role of brain Ang II in the control of neuronal development and differentiation through its regulation of the extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal cultures. The stimulation was mediated by the AT1 receptor subtype and was accompanied by an increase in PAI-1 gene transcription and the synthesis of cellular PAI-1 protein. The stimulation involved activation of protein kinase C, and alterations in the intracellular Ca2+ pool caused a significant inhibition of Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide. Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures of SH rat brain, two differences between WKY and SH rat brain neurons were observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH neurons than in WKY neurons, but c-fos antisense oligonucleotide did not attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These observations suggest that the changes in the Ang II-mediated signaling pathways and/or the regulatory region(s) of the PAI-1 gene may contribute to the differential actions of Ang II in WKY and SH rat brain neurons.
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PMID:Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 864 Dec 4

In the present study we investigated the regulation of tyrosine hydroxylase (TH) by angiotensin II (Ang II) in an attempt to provide cellular and molecular evidence that this hormone has increased neuromodulatory actions in the spontaneously hypertensive (SH) rat brain. Neuronal cells in primary culture from the hypothalamus-brain stem of both normotensive [Wistar-Kyoto (WKY)] and SH rats have been used. These cultures mimic in vivo situations. Ang II caused a time-dependent increase in TH activity in WKY rat brain neurons. A maximal increase of 2.5-fold was observed with 100 nM Ang II in an actinomycin- and cycloheximide-dependent process. In addition, Ang II caused a parallel increase in TH messenger RNA (mRNA) levels, with a maximal stimulation of 5-fold in 4 h by 100 nM Ang II in WKY rat brain neurons. The stimulation of TH mRNA was mediated by the AT1 receptor subtype, resulted from an increase in its transcription, and involved activation of phospholipase C and protein kinase C. Antisense oligonucleotide for c-fos attenuated Ang II stimulation of TH mRNA in a time- and dose-dependent fashion, indicating an involvement of c-fos as a putative third messenger in Ang II stimulation of TH. Ang II also caused stimulation of TH activity and its mRNA levels in neuronal cultures of SH rat brain by a mechanism similar to that observed for neuronal cultures of WKY rat brain, involving AT1 receptors, protein kinase C, and c-fos. However, the stimulation of TH activity and that of TH mRNA were approximately 30% and 80% higher, respectively, in the SH rat brain neurons than those in the WKY rat brain neurons. In vivo experiments have been carried out to validate the elevated response of TH gene expression to Ang II in SH rat brain neuronal cultures. Ang II stimulated both TH activity and TH mRNA levels in the hypothalami and brain stems of adult WKY and SH rats. The level of stimulation in the brain of the SH rat was significantly higher than that in the WKY rat. These observations are consistent with an increase in AT1, receptor gene expression and suggest that increased TH gene expression could be the cellular/molecular basis for the greater neuromodulatory action of Ang II in the SH rat brain.
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PMID:Angiotensin II regulation of tyrosine hydroxylase gene expression in the neuronal cultures of normotensive and spontaneously hypertensive rats. 875 88

1. The significance of protein kinase C (PKC) in respiratory pattern generation was investigated in forty-three expiratory neurones of anaesthetized cats. 2. Intracellular injection of R-2,6-diamino-N-([1-(oxotridecyl)-2-piperidinyl]-methyl)-hexana mide dihydrochloride reversibly hyperpolarized twenty-six neurones. Respiratory drive potentials decreased to 92% of control, and action potential discharges were reduced. Neuronal input resistance (Rin) decreased during inspiration and increased during expiration. 3. Voltage clamp revealed that blockade of PKC induced an increase of inhibitory drive currents and a decrease of excitatory drive currents in sixteen neurones. The amplitude of respiratory drive currents was decreased to 91% of control. The slope of synaptic inward currents during postinspiration was reduced. 4. After blockade of K+ conductances by TEA, additional blockade of PKC caused a hyperpolarization during postinspiration and expiration, but depolarization during inspiration in fourteen neurones. The respiratory drive currents were reduced to 61% of control. Respiratory drive potentials decreased to 72% of control, leading to reduced spontaneous discharge. Rin was increased throughout the respiratory cycle. 5. Stimulus-evoked postsynaptic currents and potentials decreased after blockade of PKC with and without TEA. 6. The results indicate that PKC is endogenously active in expiratory neurones, modulating their excitability in three different ways: (a) it downregulates persistent K+ currents, (b) it upregulates Cl(-)-mediated inhibitory postsynaptic currents (IPSCs), and (c) it upregulates excitatory postsynaptic currents (EPSCs).
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PMID:Protein kinase C pathways modulate respiratory pattern generation in the cat. 881 23

Neuronal factors co-released with neurotransmitters may play an important role in synapse development and function. Calcitonin gene related peptide (CGRP) and adenosine 5'-triphosphate (ATP), two principal neuromodulators present in the motor nerve terminals, were studied for their roles and mechanisms during early development of neuromuscular synapses in Xenopus nerve--muscle co-cultures. CGRP treatment increased the decay time and amplitude of spontaneous synaptic currents (SSCs) recorded from innervated myocytes, without affecting SSC frequency, suggesting a postsynaptic mechanism. ATP also increased the SSC amplitude and decay time. In addition, ATP was shown to potentiate the responses of isolated myocytes to iontophoretically applied acetylcholine (ACh). Single-channel recording from isolate myocytes showed that both CGRP and ATP specifically increased the open time of embryonic-type, low-conductance ACh channels. Pharmacological experiments suggest that the CGRP actions were mediated by cAMP-dependent protein kinase (PKA), while ATP exerted its effects by binding to P2 purinoceptors and thereby activating protein kinase C (PKC). Moreover, the effects of CGRP and ATP on ACh channel activity were restricted to immature myocytes. Taken together, these results suggest that endogenous CGRP and ATP co-released with ACh from the nerve terminal may promote synaptic development by potentiating postsynaptic ACh channel activity during the early phase of synaptogenesis.
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PMID:Regulation of postsynaptic responses by calcitonin gene related peptide and ATP at developing neuromuscular junctions. 884

We have previously described the marine toxin okadaic acid (OKA) to be a potent neurotoxin for cultured rat cerebellar neurons. Here we show that OKA-induced neurodegeneration involves the DNA fragmentation characteristic of apoptosis and is protein synthesis-dependent. DNA fragmentation and neurotoxicity correlated with inhibition of protein phosphatase (PP) 2A rather than PP1 activity. Neurotrophins NT-3 and BDNF failed to protect from OKA-induced apoptotic neurotoxicity that was, however, totally prevented by insulin-like growth factor-1. Neuronal death by OKA was significantly reduced by protein kinase C inhibitors and by the L-type calcium channel agonist Bay K8644, while it was potentiated by the reduction of free extracellular calcium concentrations.
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PMID:Inhibition of protein phosphatases induces IGF-1-blocked neurotrophin-insensitive neuronal apoptosis. 894 62

The efficacy and mechanisms of 1-amino-cyclopentyl-1S,3R-dicarboxylate (1S,3R-ACPD)-induced neuroprotection were investigated in rat hippocampal slices subjected to 10 min of oxygen and glucose deprivation. Neuronal viability was assessed by measuring both the amplitude of evoked population spike in the CA1 pyramidale and by imaging CA1 neurons using a live/dead fluorescence assay with confocal microscopy. CA1 pyramidal neurons in oxygen-glucose deprived slices remained viable for up to 120 min following the insult but were dead by 240 min. Pretreatment with 1S,3R-ACPD significantly protected the oxygen-glucose deprived slices in a concentration-dependent fashion. Oxygen-glucose deprived slices pretreated for the same period with the protein kinase C (PKC) activation phorbol 12-myristate 13-acetate (PMA; 1 microM) were significantly protected whereas oxygen-glucose deprived slices treated with the adenylyl cyclase activator, forskolin (30 microM) were not. Oxygen-glucose deprivation induced a rapid and persistent decrease (approximately 50%) in PKC activity and a > 6 fold increase in cyclic adenosine monophosphate (cAMP) levels in whole hippocampal slices. While 1S,3R-ACPD did not stimulate PKC activity and had no effect on basal cAMP in whole slices, it significantly enhanced the rate of return of cAMP to basal levels following reperfusion. Consistent with this observation, the 1S,3R-ACPD-induced neuroprotection was inhibited by forskolin (30 microM). These results suggest that in vitro neuroprotection of CA1 neurons by 1S,3R-ACPD involves metabotropic glutamate receptors negatively linked to cAMP and possibly those which increase PKC activity.
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PMID:Mechanisms of 1S,3R-ACPD-induced neuroprotection in rat hippocampal slices subjected to oxygen and glucose deprivation. 912 6


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