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

The present studies examined the relationship between protein kinase C (PKC) and L-type voltage-dependent calcium channels in modulating the release of neurotransmitter from K(+)-depolarized rat spinal cord synaptosomes. Activators of PKC, such as phorbol 12-myristate 13-acetate (PMA), mezerein and oleoyl acetylglycerol produced a concentration-dependent potentiation of K(+)-induced release of [3H]5-hydroxytryptamine ([3H]5-HT). Enhanced release was dependent on the concentration of both Ca2+ and K+ in the superfusion medium. Calcium-independent release of [3H]5-HT or release induced by the Ca2+ ionophore were unaffected by PKC activators. Calcium-dependent release of [3H]5-HT, evoked by K+, was enhanced under similar conditions by the L-type Ca2+ channel agonists Bay K 8644 and (+)-SDZ 202-791. Nimodipine, an L-type Ca2+ channel antagonist, while having no independent effect on K(+)-induced release of [3H]5-HT, abolished the potentiative effects of Bay K 8644 and PMA. Similarly, the PKC inhibitors, polymyxin B and staurosporine, blocked effects of both PMA and Bay K 8644 on K(+)-stimulated release of [3H]5-HT. Neither PMA nor Bay K 8644 altered the uptake of [3H]5-HT. These results suggest that PKC-dependent mechanisms utilize calcium influx, via the L-type calcium channel, to modulate release of neurotransmitter and indicate a possible functional link between PKC and L-type voltage-dependent calcium channels in the spinal cord.
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PMID:Protein kinase C modulates the release of [3H]5-hydroxytryptamine in the spinal cord of the rat: the role of L-type voltage-dependent calcium channels. 128 20

The role of calcium, calcium influx through calcium channels, and activation of protein kinase C for the nicotine-induced release of noradrenaline and of the sympathetic co-transmitter neuropeptide Y (NPY) was investigated in the guinea-pig isolated perfused heart. In the coronary venous overflow noradrenaline and NPY were determined by high-pressure liquid chromatography and radioimmunoassay, respectively. In the presence of extracellular calcium (1.85 mmol/l) nicotine (1-100 mumol/l) evoked a concentration-dependent overflow of both transmitters with a molar ratio of approximately 1500 (noradrenaline):1 (NPY). The nicotine-induced (100 mumol/l) overflow of noradrenaline and NPY was in a linear manner related (r = 0.79 and 0.90, respectively; p less than 0.05) to the extracellular calcium concentration (0-1.85 mmol/l), and it was prevented by calcium-free perfusion. The L-type calcium channel blocker felodipine (100 nmol/l) did not affect the nicotine-induced (100 mumol/l) transmitter overflow. On the other hand, the neuronal (N-type) calcium channel blockers omega-conotoxin (100 nmol/l) and cadmium chloride (50 mumol/l) reduced the nicotine-induced (100 mumol/l) transmitter overflow to 20% of the control value, suggesting a role of N-type calcium channels in mediating the calcium influx for the nicotine-induced transmitter release. The nicotine-induced (30 mumol/l) overflow of both transmitters was two- to three-fold increased by activation of protein kinase C (phorbol 12-myristate 13-acetate; 100 nmol/l). The transmitter overflow was unaffected by 4 alpha-phorbol 12,13-didecanoate (100 nmol/l), a phorbol ester which does not stimulate protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nicotine-induced release of noradrenaline and neuropeptide Y in guinea-pig heart: role of calcium channels and protein kinase C. 166 28

To determine whether endothelin-1 (ET-1) induces hypertrophy of cardiomyocytes, the effects of ET-1 on the expression of muscle-specific genes and a proto-oncogene, c-fos, in cultured neonatal rat cardiomyocytes were examined by Northern blot analysis. ET-1 (10(-7) M) induced about twofold to fourfold increases in the gene expression of myosin light chain 2, alpha-actin, and troponin I after 6 hours, which continued up to 24 hours. The ET-1-induced increases in mRNA levels for these muscle-specific genes were dose dependent (10(-9) to 10(-7) M). Run-on transcriptional assay showed that the changes in mRNA level for three muscle-specific genes were regulated, at least in part, at the transcriptional level. 12-O-Tetradecanoylphorbol 13-acetate (TPA), a potent protein kinase C activator, and the Ca2+ ionophore ionomycin also increased mRNA levels of three muscle-specific genes. ET-1, TPA, and ionomycin similarly induced the expression of c-fos after 30 minutes, which returned to an undetectable level after 6 hours. ET-1 remarkably and dose-dependently stimulated accumulation of total inositol phosphates in cardiomyocytes. Morphometrical evaluation showed that ET-1 significantly increased surface area of cardiomyocytes without cell proliferation. ET-1 also dose-dependently stimulated the synthesis of protein and DNA, which was unaffected by the L-type calcium channel blocker nicardipine. These data suggest that ET-1 induces hypertrophy of cardiomyocytes associated with the induction of muscle-specific gene transcripts through the possible involvement of protein kinase C activation or intracellular Ca2+ mobilization.
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PMID:Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. 205 34

The role of calcium for the release of norepinephrine (NE, determined by high-pressure liquid chromatography) and neuropeptide Y (NPY, determined by radioimmunoassay) was investigated in guinea pig perfused hearts with intact sympathetic innervation. In the presence of extracellular calcium (1.85 mM), electrical stimulation of the left stellate ganglion (12 Hz, 1 min) induced a closely related release of NE and NPY with the molar ratio of approximately 400-600 (NE) to 1 (NPY). The stimulation-evoked overflow of both transmitters was dependent from the extracellular calcium concentration and was almost completely suppressed by calcium-free perfusion. The corelease of both transmitters was not affected by the L-type calcium channel blocker felodipine (1-10 microM). However, the overflow of NE and NPY was markedly attenuated by the unselective calcium antagonist flunarizine (1-10 microM) and completely prevented by the neuronal (N-type) calcium channel blockers omega-conotoxin (1-100 nM) and cadmium chloride (10-100 microM), indicating a key role for N-type calcium channels in the exocytotic release of transmitters from cardiac sympathetic nerve fibers. Possibly due to unspecific actions, such as interference with sodium channels or uptake1-blocking properties, the phenylalkylamines verapamil (0.01-10 microM) and gallopamil (1-10 microM) reduced NPY overflow with only a minor effect on NE overflow. The stimulation-induced transmitter release was increased up to twofold by activation of protein kinase C (phorbol 12-myristate 13-acetate, 3 nM-3 microM) and completely suppressed by inhibition of protein kinase C (polymyxin B, 100 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of calcium channels and protein kinase C for release of norepinephrine and neuropeptide Y. 217 26

L-glutamate (3-1,000 microM) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 10-1,000 microM), a selective agonist for the metabotropic glutamate receptor, stimulated the formation of inositol 1,4,5-trisphosphate in a concentration-dependent manner. L-Glutamate was half as efficacious as 1S,3R-ACPD. N-methyl-D-aspartate (NMDA; 1 nM to 1 mM) did not significantly influence the response to a maximally effective concentration of 1S,3R-ACPD (100 microM). On the other hand, coapplication of (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA; 1-300 nM) produced a concentration- and time-dependent inhibition of the 1S,3R-ACPD effect, with a maximal inhibition (97%) at 100 nM. Ten micromolar 6-cyano-7-nitroquinoxaline-2,3-dione, an antagonist of the AMPA receptor, blocked the inhibitory effect of AMPA. Reduced extracellular calcium concentration, as well as 10 microM nimodipine, an L-type calcium channel antagonist, inhibited the AMPA influence on the 1S,3R-ACPD response. W-7, a calcium/calmodulin antagonist, prevented the inhibition by AMPA, whereas H-7, an inhibitor of protein kinase C, had no effect. These data suggest that activation of AMPA receptors has an inhibitory influence on inositol 1,4,5-trisphosphate formation mediated by stimulation of the metabotropic glutamate receptor. The mechanism of action involves calcium influx through L-type type calcium channels and possible activation of calcium/calmodulin-dependent enzymes.
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PMID:(R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors mediate a calcium-dependent inhibition of the metabotropic glutamate receptor-stimulated formation of inositol 1,4,5-trisphosphate. 768 1

The adenosine A2a receptor inhibition of potassium (15 mM)-evoked GABA release from striatal nerve terminals has been examined. High extracellular calcium concentrations (4 mM) reduced the effect of the A2a receptor agonist CGS-21680 (1 nM). CGS-21680 inhibited GABA release in the presence of the L-type calcium channel blocker nifedipine, which itself inhibited evoked GABA release (by 16 +/- 4%). omega-Conotoxin inhibited the evoked release by 45 +/- 4% and prevented the action of CGS-21680. Forskolin and 8-bromo cyclic AMP both stimulated evoked GABA release at low concentrations, but at higher concentrations they abolished the inhibition by CGS-21680 without affecting the evoked release. The nonselective protein kinase inhibitor H-7 inhibited both the evoked release and the inhibition by CGS-21680, whereas the selective protein kinase A and G inhibitor HA-1004 had no effect on either evoked release or the action of CGS-21680. Pretreatment with pertussis toxin did not affect the A2a receptor-mediated inhibition. Therefore, the effect of A2a receptor stimulation was not mediated by protein kinases A or G but was inhibited by elevated cyclic AMP levels and mimicked by inhibitors of the N-type calcium channel and protein kinase C.
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PMID:Inhibition of striatal GABA release by the adenosine A2a receptor is not mediated by increases in cyclic AMP. 776 61

Animal studies have demonstrated that low-level lead exposure produces hypertension and that lead can cause contraction of vascular smooth muscle directly. The physiological effects of lead have been associated with both stimulation and inhibition of protein kinase C (PKC). Given that vascular smooth muscle contractility is generally enhanced when protein kinase C is activated, we have tested the hypothesis that lead contracts vascular smooth muscle via stimulation of PKC. Helically-cut strips of rabbit mesenteric artery were mounted in muscle baths for measurement of isometric force development. Cumulative addition of lead acetate (10(-10)-10(-3) M) to the muscle bath produced contractions (concentration necessary to produce half-maximal response -log EC50 = 5.16 +/- 0.07). Maximal contraction to lead acetate in arteries denuded of endothelium did not differ from those in intact vessels, supporting the hypothesis that lead-induced contraction is an endothelium-independent event. Contractions to lead acetate were potentiated by the PKC activators, phorbol 12-myristate 13-acetate (TPA; 3 x 10(-7) M) and mezerein (3 x 10(-7) M), as indicated by leftward shifts in the concentration-response curve and increase in the potency of lead (-log EC50 with TPA: 6.94 +/- 0.07; -log EC50 with mezerein: 6.07 +/- 0.04). H-7 (6 x 10(-6) M), an inhibitor of PKC, decreased maximal contraction to lead approximately 65% and slightly, but insignificantly, decreased the potency of lead (-log EC50 = 4.82 +/- 0.1). The inactive phorbol ester, phorbol 12-myristate 13-acetate 4-0-methyl ether (1 x 10(-6) M), did not alter contractile responses to lead (-log EC50 = 4.92 +/- 0.09). Vascular contraction to lead partially depends on extracellular calcium as the L-type voltage-gated calcium channel antagonist, verapamil (3 x 10(-6) M), decreased lead-induced contractions by 50%. These data indicate that lead interacts with PKC in an endothelium-independent, calcium-dependent manner to cause vascular smooth muscle contraction and suggest that lead-induced increases in vascular contractility may play a role in lead-induced hypertension.
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PMID:Lead acetate-induced contraction in rabbit mesenteric artery: interaction with calcium and protein kinase C. 776 2

The B subunit of cholera toxin, which binds specifically to ganglioside GM1, is mitogenic for quiescent Swiss 3T3 fibroblasts. It was previously shown that the B subunit had no effect on cAMP, protein kinase C or phosphoinositide turnover, but did cause an increase in the influx of calcium from extracellular sources (Spiegel, S. and Panagiotopoulos, C. (1988) Exp. Cell Res. 177, 414-427). In contrast to the action of known growth factors, the B subunit induced significant DNA synthesis after only a 1-3 h treatment. We utilized this unique property to determine whether the increase in calcium influx plays a role in B subunit-induced mitogenicity. Cells were briefly treated with the B subunit in the presence of calcium channel blockers, followed by removal of the blockers and further incubation in B subunit-free medium for the remaining time required to measure DNA synthesis. When 1 mM cobalt was only present during the first 3 h incubation. DNA synthesis induced by either the B subunit or fetal bovine serum was completely abolished. However, both nickel (1 mM) adn the L-type voltage-gated calcium channel inhibitor nicardipin (10 microM) inhibited B subunit-induced cell proliferation without abrogating the response to fetal bovine serum. Using a gel retardation assay, we found that the B subunit markedly stimulated specific DNA-binding activity of the transcription factor, activator protein-1 (AP-1), which functions as a major convergence point coupling early events induced by a variety of mitogens to long term growth responses. Presence of c-Fos protein in the AP-1 complex was demonstrated as a supershift band in the gel mobility assay using c-Fos polyclonal antibody. Cobalt, which markedly inhibited B subunit-induced DNA synthesis, also completely abolished AP-1 DNA-binding activity stimulated by the B subunit. In sharp contrast, cobalt had no effect on DNA-binding activity of AP-1 induced by the tumor promoter, 12-O-tetradecanoylphorbol 13-acetate. Our results suggest that calcium influx is a key element for both DNA-binding activity of AP-1 and cell proliferation induced by binding of the B subunit of cholera toxin to cell surface ganglioside GM1.
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PMID:The role of calcium influx in cellular proliferation induced by interaction of endogenous ganglioside GM1 with the B subunit of cholera toxin. 778 88

We investigated species difference in binding of major neurotransmitters and intracellular second messengers in the gerbil brain and the rat brain using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]PN200-110, [3H]muscimol, [3H]MK-801, [3H]cyclohexyladenosine (CHA),and [3H]quinuclidinyl benzilate (QNB) were used to label protein kinase C, IP3 receptor, L-type calcium channel, gamma-aminobutyric acidA (GABAA) receptor, N-methyl-D-aspartate (NMDA) receptor, adenosine A1 receptor, and muscarinic cholinergic receptor, respectively. Autoradiographic distributions of the bindings of most neurotransmitters and second messengers were particularly found in the limbic system and basal ganglia in both gerbil and rat brains. However, marked differences in these bindings between the gerbil brain and the rat brain were also recognized in the above regions. In particular, among 7 ligands used, the gerbil had high [3H]PDBu and [3H]CHA binding sites throughout the brain compared to those in the rat brain except for a few areas. By contrast, the rat exhibited high [3H]MK-801 binding sites in various brain regions, as compared with the gerbil brain. Thus, the gerbil differ from the rat with respect to the binding sites of major second messengers and neurotransmitters in the brain. The results may help better elucidate the relationship or species difference between gerbils and rats for neuronal function and behavioral pharmacology.
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PMID:Autoradiographic distribution of neurotransmitter and second messenger system receptors in animal brains. 788 Apr 56

Serotonin (5-HT) contracts the guinea pig trachea through stimulation of the 5-HT2A receptor, a receptor generally linked with phosphoinositide (PI) hydrolysis. However, previous limited evidence suggested that 5-HT did not increase PI hydrolysis in guinea pig trachea. The present studies confirmed that the 5-HT2A receptor is not coupled to PI hydrolysis and investigated the calcium source and involvement of protein kinase C (PKC) in 5-HT-induced contraction in guinea pig trachea. In vitro experiments, which used an enriched tracheal muscle preparation, confirmed the inability of 5-HT (10(-10) to 10(-2) M) to increase PI hydrolysis. Short incubations (1-60 min) of the trachea with 5-HT (10(-4) M) to minimize possible 5-HT2A receptor desensitization did not increase PI hydrolysis, whereas carbamylcholine (10(-7) to 10(-3) M) and histamine (10(-7) to 10(-4) M) did. These results demonstrate that, unlike most other 5-HT2A receptors, the 5-HT2A receptor in guinea pig trachea is not coupled to PI hydrolysis. The L-type calcium channel antagonists nitrendipine (10(-6) and 10(-5) M) and diltiazem (5 x 10(-5) M) significantly blocked maximal tracheal contraction to 5-HT (45-60%) inhibition) but not to carbamylcholine. The maximal response to 5-HT in calcium-free buffer (0 calcium, 0.05 mM EGTA) was also inhibited by 56%. The residual contraction to 5-HT in the absence of extracellular calcium suggested that at least a portion of the nitrendipine-insensitive 5-HT contraction was due to the release of intracellular calcium. In support of this idea, ryanodine (3 x 10(-5) M), a compound known to deplete intracellular calcium stores, depressed maximal 5-HT contraction in the presence of either nitrendipine or diltiazem. Neither calphostin C (4 x 10(-8) and 10(-6) M) or staurosporine (10(-8) M), both putative PKC inhibitors, affected tracheal contraction to 5-HT. However, the PKC inhibitor bisindolylmaleimide (5 x 10(-6) M), which abolished contraction to phorbol 12,13-dibutyrate (10(-6) M), unlike calphostin C, inhibited contraction to 5-HT in both the absence and presence of nitrendipine. This finding suggests that PKC activation is involved in 5-HT contraction. Thus, the tracheal 5-HT2A receptor is unique in that activation of the receptor does not result in PI hydrolysis but increases calcium influx through L-type voltage-dependent calcium channels, calcium release from the sarcoplasmic reticulum and activation of a bisindolylmaleimide-sensitive PKC.
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PMID:Contractile serotonin-2A receptor signal transduction in guinea pig trachea: importance of protein kinase C and extracellular and intracellular calcium but not phosphoinositide hydrolysis. 796 3


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