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)

Clinical implications of three areas of basic neuroscience research are described in this review paper. These areas include: (1) the discovery of protein kinase C and its implications for diabetic neuropathy, (2) analysis of single ionic channels and the basis of Lambert-Eaton myasthenic syndrome and cystic fibrosis, and (3) the cloning of genes for Duchenne muscular dystrophy and cystic fibrosis and new approaches to the treatment of these diseases.
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PMID:Clinical implications of basic neuroscience research. I: Protein kinases, ionic channels, and genes. 165 49

A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy, but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol, which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic, streptozocin-induced diabetic, and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.
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PMID:Normalization of Na(+)-K(+)-ATPase activity in isolated membrane fraction from sciatic nerves of streptozocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro. 185 Jul 4

A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.
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PMID:A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration. 218 78

Diminished Na+-K+-ATPase activity in diabetic peripheral nerve plays a central role in the early electrophysiological, metabolic, and morphological abnormalities of experimental diabetic neuropathy. The defect in Na+-K+-adenosinetriphosphatase (ATPase) regulation in diabetic nerve is linked experimentally to glucose- and sorbitol-induced depletion of nerve myo-inositol but is not fully understood at a molecular level. Therefore, regulation of nerve Na+-K+-ATPase activity by phosphoinositide-derived diacylglycerol was explored as the putative link between myo-inositol depletion and the Na+-K+-ATPase impairment responsible for slowed saltatory conduction in diabetic animal models. In vitro exposure of endoneurial preparations from alloxan-diabetic rabbits to two protein kinase C agonists, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate and 1,2-(but not 1,3-) dioctanoyl-sn-glycerol, for as little as 1 min completely and specifically corrected the 40% decreased enzymatically measured ouabain-sensitive ATPase activity. Neither of these agonists affected ouabain-sensitive ATPase activity in endoneurial preparations derived from nondiabetic controls. These observations are compatible with the hypothesis that metabolites of electrically stimulated phosphoinositide turnover such as diacylglycerol acutely regulate nerve Na+-K+-ATPase activity, probably via protein kinase C, thereby tightly coupling energy-dependent Na+-K+-antiport with impulse conduction in peripheral nerve. Glucose-induced depletion of myo-inositol presumably limits phosphoinositide turnover and diacylglycerol production, thereby disrupting this putative regulatory mechanism for Na+-K+-ATPase in diabetic peripheral nerve.
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PMID:In vitro correction of impaired Na+-K+-ATPase in diabetic nerve by protein kinase C agonists. 253 78

Diabetic neuropathy, long-recognized as an important but complex and poorly understood clinical complication of diabetes, is finally yielding to more than a decade of intense clinical and laboratory investigation. At least one basic biochemical mechanism involving sorbitol and MI metabolism, phosphoinositides, protein kinase C, and the (Na,K)-ATPase has been identified that can rationally account for the neurotoxicity of glucose. This biochemical sequence has been examined in some detail in vitro, but some of its elements, such as the link between abnormal sorbitol and MI metabolism, and between protein kinase C and the (Na,K)-ATPase, remain the subject of ongoing investigation. Through its effect on the (Na,K)-ATPase, this metabolic sequence can explain both the rapidly-reversible functional impairment and the early structural lesions of nerve fibers, such as paranodal swelling in acute diabetes. Extrapolation of early paranodal swelling to the more advanced stages of nerve fiber damage remains somewhat speculative, although axo-glial dysjunction is a likely intermediate step. Impaired axonal transport or microvascular dysfunction may be additional contributing factors, possibly also related to abnormal sorbitol and MI metabolism. Blunted phosphoinositide-mediated signal transduction could potentially explain a putative insensitivity to neurotrophic factors and a diminished regenerative response in diabetic neuropathy. Human morphometric studies and ARI trials support the relevance of these pathogenetic processes to human diabetic neuropathy, and suggest that specific metabolic therapy with agents such as ARIs hold promise as important new elements in the treatment and possibly prevention of diabetic neuropathy.
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PMID:Pathogenesis and prevention of diabetic neuropathy. 329 48

1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.
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PMID:Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. 798 28

Defective protein kinase C (PKC) has been implicated in impaired Na+,K(+)-ATPase activity in the sciatic nerve of streptozotocin-induced diabetic rats. In the present study, alpha, beta I, beta II, gamma, delta, and epsilon isoform-specific antibodies were used in parallel to the measurement of compound PKC activity for the characterization of PKC distribution and isoform expression in sciatic nerves of normal and diabetic rats. To distinguish isoform expression between the axonal and glial compartments, PKC isoforms were evaluated in nerves subjected to Wallerian degeneration and in a pure primary Schwann cell culture. alpha, beta I, beta II, delta, and epsilon but no gamma isoforms were detected in sciatic nerve. Similar immunoreactivity was observed in degenerated nerves 3-4 days after transection except for diminished beta I and epsilon species; in Schwann cell cultures, only alpha, beta II, delta, and epsilon were detected. In normal nerves, two-thirds of PKC compound activity was found in the cytosol and 50% of total enzyme activity translocated to the Na+,K(+)-ATPase-enriched membrane fraction with phorbol myristate acetate. Similar redistribution patterns were observed for the immunoreactivity of all isoforms with the exception of delta, which did not translocate to the membrane with phorbol myristate acetate. No abnormality in compound PKC activity, in the immunoreactive intensity, or in the distribution of PKC isoforms could be detected in rat sciatic nerve after 6-12 weeks of diabetes. Thus, defective activation rather than decreased intrinsic PKC activity may occur in diabetic neuropathy.
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PMID:Alpha, beta I, beta II, delta, and epsilon protein kinase C isoforms and compound activity in the sciatic nerve of normal and diabetic rats. 829 31

Changes in the expression and activation of protein kinase C (PKC) have been implicated in the pathogenesis of diabetic neuropathy. Recent studies in liver, retina, and cardiovascular tissues from experimentally diabetic rats have demonstrated that diabetes has a selective effect on the expression and subcellular distribution of isozymes of PKC. In the light of this evidence, we investigated the expression of the PKC isozymes alpha, betaI, betaII, and gamma in sciatic nerves, spinal cords, and in the L4,5 dorsal root ganglia from streptozotocin-induced diabetic rats. Six weeks of diabetes had differential effects on the expression and distribution of PKC isozymes in sciatic nerves and spinal cords. In the sciatic nerves there was an apparent translocation of the alpha isoform from the cytosolic to the particulate fractions, the betaII isoform was reduced in the cytosolic fraction, and the betaI and gamma isoforms were unaffected. The changes in the isozyme immunoreactivities in the nerves were not a direct result of changes in either spinal cord or dorsal root ganglia alone, suggesting that diabetes has different effects on motor and sensory fibres and/or on Schwann cells. In nerves that had been crushed 14 days previously there was an increase in total PKC alpha immunoreactivity. This increase was potentiated in diabetic rats. On the other hand, PKC betaII immunoreactivity in crushed nerves was unaffected by diabetes. The data are consistent with diabetes-induced changes in expression of PKC betaII contributing to nerve damage, and changes in PKC alpha being a consequence of it.
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PMID:Protein kinase C isozyme expression in sciatic nerves and spinal cords of experimentally diabetic rats. 913 70

Oxidative stress has been related to the development of diabetic neuropathy. Experimental diabetes (alloxan injection of mice) promotes early biochemical changes in peripheral nervous tissue, e.g. decrease in Na,K-ATPase activity and glutathione (GSH) peroxidase (GSHPx) activity. The former decrease can be reverted by inhibiting protein kinase C (PKC), since it has been reported that PKC is activated in these experimental conditions. Here we present data demonstrating that the inhibition of PKC, as early as 4 days after alloxan administration, is not able to return to normal values GSHPx activity in sciatic nerve of diabetes mice. Thus, it would fit with our previous proposal of the possible glycation of this protein as an early event in experimental diabetes, and apparently rules out the control of GSHPx activity by PKC in this tissue.
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PMID:Experimental diabetic neuropathy: role of oxidative stress and mechanisms involved. 969 7

We investigated the relation between cyclic AMP (cAMP) and nitric oxide (NO) production, as well as the effect of NO on Na , K+-ATPase activity in the human neuroblastoma cell line SH-SY5Y. Two cAMP agonists, dibutyryl cAMP (DBC) and beraprost sodium (BPS), increased cAMP accumulation and NO production in a time and dose dependent manner at 50 mmol/l glucose. On the other hand, cellular sorbitol and myo-inositol contents and protein kinase C activity were not altered by DBC or BPS. A specific protein kinase A inhibitor, H-89, suppressed increases in nitrite/nitrate and cyclic GMP (cGMP) and protein kinase A activity stimulated by DBC or BPS. This finding suggests that cAMP stimulates NO production by activating protein kinase A via a pathway different from the sorbitol-myo-inositol-protein kinase C pathway. We observed that an NO donor, sodium nitroprusside, and an NO agonist, L-arginine, enhanced ouabain sensitive Na+, K+-ATPase activity at 50 mmol/l glucose. We also found that a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited Na+, K+-ATPase activity at 5 mmol/l glucose, and partially suppressed the enzyme activity stimulated by DBC or BPS. The results of this study suggest that cAMP regulates protein kinase A activity, NO production and ouabain sensitive Na+, K+-ATPase activity in a cascade fashion. The results also suggest that protein kinase A at least partially regulates Na+, K+-ATPase activity without mediation by NO in SH-SY5Y cells. We speculate that cAMP and NO are two important regulatory factors in the pathogenesis of diabetic neuropathy.
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PMID:cAMP regulates nitric oxide production and ouabain sensitive Na+, K+-ATPase activity in SH-SY5Y human neuroblastoma cells. 986 12


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