Protein kinase C: is its pivotal role in cellular activation over-stated?

doi:10.1016/0165-6147(94)90110-4

Trends in Pharmacological Sciences

Volume 15, Issue 2, February 1994, Pages 53-57

https://doi.org/10.1016/0165-6147(94)90110-4 Get rights and content

Abstract

Evidence has emerged over the past decade to suggest that protein kinase C (PKC) is a widespread family of kinases responsible for many diverse and critical cellular functions. With the development of selective agents to activate or inhibit the individual PKC isoenzymes, it is now apparent that much of the literature that implicated PKC in many cellular functions needs to be appraised. In this article, Sandra Wilkinson and Trevor Hallam discuss the problems of the existing methods and the recent evidence that suggests that PKC isotypes are necessary for some, but not all, of those cellular responses where PKC had been thought to play an important role. Selective inhibitors of PKC isoenzymes may have potential for therapeutic use in auto-immune diseases, transplant rejection and oncology.

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The effects of a novel adenosine A₃ receptor antagonist, SSR161421, were examined on both antigen per se and adenosine receptor agonist-increased airway responses in antigen-sensitized guinea pigs. Adenosine (10⁻⁵ M) and AB-MECA [N6-(4-aminobenzyl)-adenosine-5′-N-methyl-uronamide dihydrochloride] (10⁻⁷ M) increased the antigen response up to 61±3.0% and 88±5.2% of maximal contraction, respectively. The agonists of adenosine A₁ and A₂ adenosine receptors NECA [1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-b-d-ribofuranuronamide-5′-N-ethylcarboxamidoadenosine], R-PIA [N⁶-R-phenylisopropyladenosine], and CGS21680 (10⁻⁷ M) were ineffective. In vivo intravenous adenosine (600 μg/kg) and AB-MECA (30 μg/kg) increased the threshold antigen dose-induced bronchoconstriction by 214±13.0% and 220±15.2%, respectively. SSR161421 in vitro (IC₅₀=5.9×10⁻⁷ M) inhibited the AB-MECA-enhanced antigen-induced airway smooth muscle contractions and also in vivo the bronchoconstriction following either intravenous (ED₅₀=0.008 mg/kg) or oral (ED₅₀=0.03 mg/kg) administration in sensitized guinea pigs. Antigen itself could evoke tracheal contraction in vitro and bronchoconstriction in vivo in antigen-sensitized guinea pigs. SSR161421 (3×10⁻⁶ M) decreased the AUC of the antigen-induced contraction-time curve to 20.8±5.4% from the 100% control level. SSR161421 effectively reversed the antigen-induced bronchoconstriction, plasma leak and cell recruitment with EC₅₀ values of 0.33 mg/kg p.o., 0.02 mg/kg i.p. and 3 mg/kg i.p., respectively.
Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by α2 adrenoceptor agonist dexmedetomidine
2011, European Journal of Pharmacology
Citation Excerpt :
As with PD98059, U0126 (50 μM) attenuated control 4-aminopyridine (1 mM)-evoked glutamate release and occluded the inhibitory effect of dexmedetomidine on 4-aminopyridine-evoked glutamate release. However, in the presence of staurosporine at concentrations (1 μM) that inhibit protein kinase C and protein kinase A activities (Wilkinson and Hallam, 1994), the inhibitory action of dexmedetomidine on 4-aminopyridine-evoked glutamate release was unaffected [F(1, 11) = 30.051, P < 0.05]. Similar results were observed with the protein kinase C inhibitor bisindolylmaleimide I (GF109203X) (10 μM) [F(1, 10) = 60.206, P < 0.05], or the protein kinase A inhibitor 2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo-benzodiazocine-10-carboxylic acid-hexyl ester (KT5720) (10 μM) [F(1, 10) = 86.999, P < 0.05, Fig. 5B)].
The present study examined the effect of dexmedetomidine, an α₂ adrenoceptor agonist, on endogenous glutamate release in rat cerebral cortex nerve terminals (synaptosomes). We also explored the possible mechanism that triggers dexmedetomidine to act. Dexmedetomidine dose-dependently inhibited the release of glutamate evoked by the K⁺ channel blocker 4-aminopyridine. Presynaptic α_2A adrenoceptors were involved in this release inhibition, with the α_2A antagonist (but not by the α_2B/C antagonist) blocking the dexmedetomidine-mediated inhibition. The effect of dexmedetomidine on the evoked glutamate release was prevented by the chelating extracellular Ca²⁺ ions, and by the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate did not have any effect on the action of dexmedetomidine. Dexmedetomidine decreased the degree of depolarization-induced increase in the intrasynaptosomal Ca²⁺ levels, but did not affect the synaptosomal membrane potential. The inhibitory effect of dexmedetomidine on evoked glutamate release was abolished by blocking the Ca_v2.2 (N-type) and Ca_v2.1 (P/Q-type) channels, but was insensitive to the endoplasmic reticulum ryanodine receptors or mitochondrial Na⁺/Ca²⁺ exchange. In addition, the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors prevented dexmedetomidine from inhibiting glutamate release. Further, western blotting showed that dexmedetomidine decreased the 4-aminopyridine-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 and synapsin I, the main presynaptic target of mitogen-activated protein kinase. Thus, we concluded that dexmedetomidine acts at α_2A adrenoceptors present on cerebrocortical nerve terminals inhibit the release of glutamate. We further concluded that this effect is linked to the suppression of voltage-dependent Ca²⁺ channels and mitogen-activated protein kinase activity.
Inhibition of glutamate release by bupropion in rat cerebral cortex nerve terminals
2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
As with PD98059, although U0126 (50 μM) attenuated control 4-AP (1 mM)-evoked glutamate release (3.5 ± 0.1 nmol/mg/5 min; P < 0.01), it also occluded the inhibitory effect of bupropion on 4-AP (1 mM)-evoked glutamate release (3.1 ± 0.2 nmol/mg/5 min) (Fig. 7). However, in the presence of staurosporine at concentrations (1 μM) that inhibit PKC and PKA activities (Wilkingson and Hallam, 1994), the inhibitory action of bupropion on 4-AP-evoked glutamate release was unaffected (Fig. 7). Similar results were observed with the PKC inhibitor GF109203X (10 μM), the PKA inhibitor H89 (10 μM), or the CaMKII inhibitor KN62 (50 μM) (Fig. 7).
Central glutamate neurotransmission has been postulated to play a role in pathophysiology of depression and in the mechanism of antidepressants. The present study was undertaken to elucidate the effect and the possible mechanism of bupropion, an atypical antidepressant, on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Result showed that bupropion exhibited a dose-dependent inhibition of 4-aminopyridine (4-AP)-evoked release of glutamate. The effect of bupropion on the evoked glutamate release was prevented by the chelating the intrasynaptosomal Ca²⁺ ions, and by the vesicular transporter inhibitor, but was insensitive to the glutamate transporter inhibitor. Bupropion decreased depolarization-induced increase in [Ca²⁺]_C, whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The effect of bupropion on evoked glutamate release was abolished by the N-, P- and Q-type Ca²⁺ channel blocker, but not by the ryanodine receptor blocker, or the mitochondrial Na⁺/Ca²⁺ exchanger blocker. In addition, the inhibitory effect of bupropion on evoked glutamate release was prevented by the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors. Western blot analyses showed that bupropion significantly decreased the 4-AP-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), and this effect also was blocked by MEK inhibitor. These results are the first to suggest that, in rat cerebrocortical nerve terminals, bupropion suppresses voltage-dependent Ca²⁺ channel and MEK/ERK activity and in so doing inhibits evoked glutamate release. This finding may provide important information regarding the beneficial effects of bupropion in the brain.
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The antioxidant α-lipoic acid has been reported to prevent and reverse age-related impairments in learning and memory. However, it is unclear how α-lipoic acid improves cognitive function. In this study, the effect of α-lipoic acid on the release of endogenous glutamate from rat cerebrocortical nerve terminals (synaptosomes) was examined. We found that α-lipoic acid potently facilitated 4-aminopyridine (4AP)-evoked glutamate release, and this release facilitation results from an enhancement of vesicular exocytosis and not from an increase of non-vesicular release. Examination of the effect of α-lipoic acid on cytosolic [Ca²⁺] revealed that the facilitation of glutamate release was associated with an increase in voltage-dependent Ca²⁺ influx. Consistent with this, α-lipoic acid-mediated facilitation of glutamate release was completely prevented in synaptosomes pretreated with a wide spectrum blocker of the N- and P/Q-type Ca²⁺ channels, ω-conotoxin MVIIC. The facilitatory effect of α-lipoic acid on Ca²⁺ influx was not due to an increase of synaptosomal excitability because α-lipoic acid did not alter the 4AP-evoked depolarization of the synaptosomal plasma membrane potential. In addition, both ionomycin and hypertonic sucrose-induced glutamate release were enhanced by α-lipoic acid. Furthermore, disruption of cytoskeleton organization with cytochalasin D occluded the facilitatory effect of α-lipoic acid on 4AP or ionomycin-evoked glutamate release. These results suggest that the antioxidant α-lipoic acid enhances the Ca²⁺ entry through presynaptic N- and P/Q-type Ca²⁺ channels as well as the vesicular release machinery to cause an increase in evoked glutamate release from rat cerebrocortical synaptosomes. Also, activation of PKA and PKC may underlie, at least in part, the α-lipoic acid-mediated facilitation of glutamate release observed here as α-lipoic acid-enhanced 4AP and ionomycin-evoked glutamate release were significantly attenuated by PKA and PKC inhibitors. This finding may provide some information regarding the mechanism of action of α-lipoic acid in the central nervous system (CNS).
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The importance of cytokines and the complement system in the propagation and maintenance of the brain inflammatory response to injury are emphasised. Much data supports the case that ischemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, complement activation, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now better understood. In this review, we discuss the role of TNFα and IL-1β in traumatic and brain injury and associated inflammation, and the co-operative actions of the complement system, chemokines and adhesion molecules in this process. Celluar stress and cellular stress signalling is key to the neurodegenerative process in brain injury. Therefore, we also address novel approaches to target cytokines and reduce the brain inflammatory response, and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated, and treatment with p38 MAPK inhibitors can provide a significant reduction in infarct size, neurological deficits and increased inflammatory cytokines/proteins expression produced by focal stroke. p38 MAPK inhibition can also provide direct protection of cultured brain tissue to in vitro ischemia. This robust neuroprotection that can be produced by inhibition of p38 MAPK signalling emphasizes a significant opportunity for targeting MAPK pathways CNS injury/disease. Many examples of the roles of inflammation, cellular oxidative stress and MAPK signalling in Psychiatric and Neurodegenerative Diseases are also provided. As a whole, the available data suggests that inflammation, cellular stress and p38 MAPK signalling are important in nervous disease pathologies and that inhibition of cellular stress signalling should be considered for improving outcome in many CNS diseases.
4α-Phorbol negates the inhibitory effects of phorbol-12-myristate-13-acetate on human cilia and alters the phosphorylation of PKC
2002, FEBS Letters
Citation Excerpt :
The effects of other modulators remain to be explained and we report three unexpected effects on the pattern of decline in CBF compared to that observed in M199. Firstly, BIMI, the selective inhibitor of classical and some novel PKC (δ and ϵ) isoforms [32–35] decreases CBF in a linear fashion. This decline was not seen with MyrPKCI.
In medium 199, ciliary beat frequency (CBF) in human nasal epithelium declines to 60% of baseline by 2 h and 1 nM phorbol-12-myristate-13-acetate (PMA) doubles the rate of decline by activating protein kinase C (PKC). We find that a reported negative control for PMA, 4α-phorbol (1 pM–1 nM)±1 nM PMA, not only maintains CBF at baseline, but arrests a pre-existing PMA-induced decline in CBF and alters the profile of multiple phosphorylated PKC species. Thus, 4α-phorbol not only potently prevents PMA from inhibiting CBF but also has potent effects on the phosphorylation of PKC.

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Trends in Pharmacological Sciences

Protein kinase C: is its pivotal role in cellular activation over-stated?

Abstract

J. Biol. Chem.

Trends Biochem. Sci.

Trends Biochem. Sci.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

Cell Signalling

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

Clin. Exp. Rheumafology

Biochem. J.