Disease relevance of PKC

• The protein kinase C (PKC) pathway has recently been recognized as an important mechanism in the development of diabetic complications including cardiomyopathy and angiopathy [1].
• We now determine the role of protein kinase C (PKC) in ethanol's protective effect against ischemia-reperfusion injury [2].
• Currently at least 11 protein kinase C (PKC) isoforms have been identified and may play different roles in cell signaling pathways leading to changes in cardiac contractility, the hypertrophic response, and tolerance to myocardial ischemia [3].
• Permeabilization in a cerebral endothelial barrier model by pertussis toxin involves the PKC effector pathway and is abolished by elevated levels of cAMP [4].
• Before ischemia, hearts were either untreated or treated with sevoflurane (APC) in the absence or presence of the nonspecific PKC inhibitor chelerythrine, the PKC-delta inhibitor PP101, or the PKC-epsilon inhibitor PP149 [5].

High impact information on PKC

• The PKC-induced phosphorylation did not affect Kit/SCF-R ligand binding affinity [6].
• In contrast, PKC was necessary for SCF-induced motility responses, including actin reorganization and chemotaxis [6].
• We tested the hypothesis that nifedipine can prevent ischemia-induced endothelial permeability increases by inhibiting protein kinase C (PKC) in cultured porcine endothelial cells [7].
• Instead, ischemia-induced PKC translocation was prevented by nifedipine [7].
• Using perfused hearts of ethanol-fed guinea pigs, we find that improved contractile recovery and creatine kinase release after ischemia-reperfusion are abolished by PKC inhibition with chelerythrine [2].

Chemical compound and disease context of PKC

• Our findings suggest (i) that regular ethanol consumption induces long-term cardioprotection through sustained translocation of epsilonPKC and (ii) that PKC activity is necessary at the time of ischemia to mediate ethanol's protective effect against ischemia-reperfusion injury [2].
• These data lead us to suggest that fMLP- and PAF-stimulated arachidonic acid release is mediated by mechanisms involving either a staurosporine-insensitive PKC isoform or a sphingosine-sensitive coupling between a pertussis toxin-sensitive guanine nucleotide-binding protein and phospholipase A2 [8].
• Pertussis toxin activates L-arginine uptake in pulmonary endothelial cells through downregulation of PKC-alpha activity [9].
• Because previous data showed prostaglandin I2 at subdilator concentrations can also return dilation to hypercapnia to piglets treated with indomethacin, prostaglandin I2 could provide its permissive input by activating PKC and/or inhibiting PTK [10].
• One-hour exposure to 10 microM PMA, to down-regulate PKC, blocked vasodilation to hypercapnia but did not inhibit vasodilation to sodium nitroprusside [10].

Biological context of PKC

• Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes [1].
• Attenuation of CaMKII activity by PKC showed strong similarity to the downregulation of CaMKII by basal autophosphorylation [11].
• (5) Since both kinase modulators, TPA and KN-62, affected no divergent signal transduction pathways in the parietal cell, an in vitro model has been used to study if PKC directly targets CaMKII [11].
• Protein kinase C (PKC) is activated at the cell membrane by interacting with both the acidic lipid phosphatidylserine and the second messenger diacylglycerol [12].
• We conclude that in the adult heart, LV dilation produced stretch-mediated activation of phospholipase C, which resulted in PI hydrolysis and PKC epsilon activation in part by stimulation of the local renin angiotensin system [13].

Anatomical context of PKC

• We conclude that an increase in extracellular glucose leads to a rapid dose-dependent increase in endothelial cell permeability via the activiation of PKC and that this effect is mediated by the PKC isoform alpha [14].
• Modulation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) disrupts the cell-cell junctions of the epithelial cell line LLC-PK1 [15].
• These results indicate that the alpha isoform of PKC is at least one of the isoforms that regulate tight junctions and other cell-cell junctions of LLC-PK1 epithelia [15].
• CaMKII purified from parietal cell-containing gastric mucosa of pig, was transphosphorylated by purified cPKC containing PKC-alpha up to 1.8 mol P(i) per mol CaMKII in vitro [11].
• (1) The phorbolester 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C (PKC), inhibits cholinergic stimulation of gastric acid secretion [11].

Associations of PKC with chemical compounds

• In this study we assessed quantitatively the mRNA and protein expression profiles of PKC isozymes in the heart and vascular tissues from streptozotocin-induced diabetic pigs [1].
• High glucose activates protein kinase C (PKC), a family of kinases vital to intracellular signaling [14].
• To examine the role of specific PKC isoforms in this process we have created modified LLC-PK1 subclones that express wild-type and dominant negative versions of PKC-alpha under control of the tetracycline-responsive expression system [15].
• (3) Gö 6976, an inhibitor of calcium-dependent PKC, concentration-dependently antagonized the inhibitory effect of TPA, and, therefore, revealed the action of PKC-alpha on carbachol-induced acid secretion in rabbit parietal cells [11].
• Calphostin C, a PKC inhibitor, abrogated the FB(1)-induced translocation of PKCalpha [16].

Physical interactions of PKC

• From the present data, we conclude that in tracheal smooth muscle, muscarinic acetylcholine receptor-induced PLD activation is transient in nature and coupled to these receptors via PKC [17].

Regulatory relationships of PKC

• However, it is presently not clear whether PKC is activating the same population of channels as PKA or a separate class of Cl- channels. even though the regulatory (R) domain of CFTR is known to contain consensus phosphorylation sites for both PKA and PKC [18].
• In contrast, the IGFBP-5 expression induced by forskolin was unaffected by PKC down-regulation or inhibition, suggesting that PKC activation is required for the IGF-regulated but not the cAMP-regulated events [19].
• When these reductions of connexin-43 were blocked by protein kinase C (PKC) or phosphatidylinositol (PI) 3-kinase inhibitor, networks of filamentous bivalents (i.e., advanced chromosomal status) were undetectable in the germinal vesicle of the oocyte [20].
• These results are consistent with the view that activation of PKC provides at least one intracellular mechanism that regulates relaxin secretion by porcine luteal cells [21].
• Finally, the partial inhibitory effect of a protein kinase C (PKC) inhibitor, bisindolylmaleimide, on EGF-stimulated LDH A mRNA supports a partial involvement of PKC in the action of the growth factor [22].

Other interactions of PKC

• By contrast, phorbol myristate acetate (PMA, 200 nM), a potent activator of PKC, induced a relocalization of PKC alpha from the C to the PM [23].
• (6) The phosphotransferase activity of the purified CaMKII was in vitro inhibited after transphosphorylation by PKC if calmodulin was absent during transphosphorylation [11].
• The involvement of protein kinase C (PKC) in vasopressin-induced effects on renal water reabsorption is still unresolved [23].
• Leptin led to a nitric oxide (NO) synthase (NOS)-specific, dose-dependent increase in NO production from PBMCs because leptin-induced NO release was blocked by the addition of the NOS inhibitor Nomega-Nitro-l-arginine methyl ester and protein kinase C (PKC) inhibitor calphostin C [24].
• Treatment of the arteries with phorbol 12-myristate 13-acetate, a potent stimulator of PKC, induced ICAM-1 expression and enhanced the endothelial adhesiveness to PMNs and PMN-induced EDR impairment, mimicking the effects of Ox-LDL [25].

Analytical, diagnostic and therapeutic context of PKC

• Partial regions of the porcine PKCalpha, beta1, and beta2 mRNAs were sequenced, and real-time RT-PCR assays were developed for PKC mRNA quantification [1].
• Western blot analysis revealed that guinea pig pancreatic ducts express the alpha, beta1, delta, epsilon, eta, theta, zeta and mu isoforms o f PKC [26].
• PKC isoforms were assessed by Western blot and confocal microscopy [7].
• PKC activity was measured by substrate phosphorylation after cell fractionation [7].
• Because activation of protein kinase C (PKC) mediated via alpha-adrenergic receptor stimulation is also known to regulate several ion channels, the idea that activation of PKC also can induce ICl was investigated by using isolated feline ventricular myocytes and the whole-cell patch-clamp technique [27].

References