EC:2.7.11.13 - FACTA Search

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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 aim of this study was to determine how the contractile responses to 5-hydroxytryptamine (5-HT) are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence of extracellular Ca2+ (2.5 mM), the contractile responses to stimulation of 5-HT2 receptors with 5-HT were greater in aortas from diabetic rats as compared with those from age-matched controls. Similarly, phorbol-12,13-dibutyrate (PDBu) (> or = 30 nM) induced significantly greater contractions in diabetic aortas. The enhanced contractile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 microM nifedipine. Pretreatment with 20 nM staurosporine caused a complete inhibition of the contractile responses to 5-HT in both control and diabetic aortas. In contrast to those to 5-HT and PDBu, the contractile responses to high K+ (40 mM) were markedly diminished in diabetic aortas. The nifedipine-sensitive uptake of 45Ca2+ induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K+ was significantly less in diabetics. The phasic contractions produced by 5-HT in Ca(2+)-free medium were significantly attenuated in diabetic aortas, but those produced by norepinephrine were unchanged. Accumulation of [3H]inositol monophosphate (IP1) in aortic strips prelabeled with myo-[3H]inositol was increased to a similar extent by 5-HT and norepinephrine in control rats, but the 5-HT-induced increase in [3H]IP1 accumulation was significantly less than the norepinephrine-induced one in diabetics. These findings indicate that the extracellular Ca(2+)-dependent contractions mediated by 5-HT2 receptors are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transmembrane Ca2+ channels as a consequence of increased protein kinase C activated processes. On the other hand, the contraction induced by release of Ca2+ from intracellular stores in response to 5-HT is diminished in these tissues, possibly due to the impaired phosphoinositide response.
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PMID:Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity. 765 79

It has been shown that chronic lung diseases which increase the concentration of pulmonary carbon dioxide (CO2) at the expense of oxygen stimulate the secretion of biogenic amines and neuropeptides by pulmonary neuroendocrine cells (PNE cells) in man and laboratory animals. This increase in secretory activity is always accompanied by hyperplasia of PNE cells, and smokers with chronic obstructive lung disease are at high risk for the development of neuroendocrine lung cancer. We have previously shown that nicotine and the structurally related nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), stimulate the proliferation of neuroendocrine cell lines derived from lung carcinoid tumors via interaction with nicotinic acetylcholine receptors (nAChR). In our current experiment, we have addressed the mechanisms of cell proliferation in response to nicotine and NNK in normal PNE cells derived from fetal hamster lungs, and two cell lines derived from human neuroendocrine lung cancers. Our data show that in these systems the mitogenic effects of nicotine and NNK are potentiated in a concentration-dependent manner by elevated levels of CO2, an effect blocked by inhibitors of protein kinase C(PKC) and reduced by antagonists of receptors for 5-hydroxytryptamine (5-HT, serotonin) and mammalian bombesin. The observed effects of CO2 were saturable and independent of changes in the acidity of the tissue culture media. Our data suggest that increases in CO2 concentration at the expense of oxygen may stimulate signal transduction pathways in normal and neoplastic neuroendocrine lung cells thus enhancing their susceptibility to the mitogenic effects of tobacco-specific toxicants.
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PMID:Carbon dioxide potentiates the mitogenic effects of nicotine and its carcinogenic derivative, NNK, in normal and neoplastic neuroendocrine lung cells via stimulation of autocrine and protein kinase C-dependent mitogenic pathways. 771 58

Vasoconstricting agonists elevate the intracellular Ca2+ concentration and induce tension development in vascular smooth muscle cells by inducing both Ca2+ influx from the extracellular space and Ca2+ release from cellular stores. The relative importance of Ca2+ release has been found to vary between different sites in the vasculature. This review examines the role of Ca2+ release in the activation of cerebral arteries produced by several vasoconstricting stimuli. Although the activation of cerebral arteries by agonists such as 5-hydroxytryptamine and noradrenaline has typically been found to have little dependence on Ca2+ release, other vasoconstrictors such as thromboxane A2, which may be released from the endothelium by other agonists, appear to induce a substantial intracellular Ca2+ release in cerebral arteries. The limited efficacy of Ca2+ influx blockers in the treatment of delayed cerebrovascular constriction occurring as a result of subarachnoid haemorrhage suggests that intracellular mechanisms such as Ca2+ release and/or the activation of protein kinase C may be important determinants of vasoconstriction under pathological conditions.
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PMID:Intracellular Ca2+ release in cerebral arteries. 772 59

The vasculature of rat isolated mesentery and small intestine was perfused with a gelatin-containing physiological salt solution (GPSS). When 5-hydroxytryptamine (5HT, 1 x 10(-4) M), or the calcium ionophore A23187 (1 x 10(-4) M), or 12-deoxyphorbol 13-phenylacetate (DOPPA, 1 x 10(-6) M), or 12-deoxyphorbol 13-phenylacetate 20-acetate (DOPPAA, 1 x 10(-6) M) or thymeleatoxin (TMX, 1 x 10(-6) M) was added to the GPSS for 5 min there was a gradual rise in perfusion pressure, whereas resiniferatoxin (RFX, 1 x 10(-6) M) was without effect. Pre-treatment of the tissue with the protein kinase C (PKC) inhibitor Ro 31-8220 (1 x 10(-6) M) significantly reduced the rise in perfusion pressure in response to 5HT, DOPPA, DOPPAA and TMX, but not that to A23187. Platelet-activating factor (PAF, 5 x 10(-6) M) caused an almost immediate but transient rise in perfusion pressure, followed by a more gradual rise, neither response being blocked by Ro 31-8220. When blood vessels of the mesentery alone were perfused with gelatin-free PSS, PAF caused a transient rise in perfusion pressure, but with no subsequent gradual rise over 5 min. After Ca(2+)-depletion this transient response was also absent. In contrast, when blood vessels were perfused with gelatin-free PSS, DOPPA and TMX still caused gradual rises in perfusion pressure, which were totally abolished by Ro 31-8220. TMX had no effect at all when the tissue was depleted of Ca2+, whereas the response to DOPPA was only partially reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoconstriction in rat isolated mesentery and small intestine in response to various activators of protein kinase C. 774 Oct 37

Desensitization of platelets to 5-hydroxytryptamine (5HT) (1 microM), during active removal of the agonist by the platelet 5HT-uptake system, was studied at the level of signal transduction. Desensitization to 5HT was dose-dependent and homologous. Without occupation of the 5HT2 receptor, neither an increase in cytosolic [Ca2+] (30 nM ionomycin), nor a separate or simultaneous activation of protein kinase C (by 10 microM 1-oleoyl-2-acetylglycerol), could induce desensitization to 5HT (1 microM). During the early phase of desensitization, the 5HT2 receptor was coupled to phospholipase C, whereas during the late phase of desensitization this coupling was disconnected. However, after disappearance of the agonist, the coupling in the resting platelet recovered quickly, and was nearly complete (82%) after 30 min. During this resensitization, the 5HT-inducibility of activation of phospholipase C, of the increase in cytosolic [Ca2+] and of stimulation of protein kinase C were restored in parallel. The time course for resensitization of the 5HT-induced increase in cytosolic [Ca2+] was independent of the presence of extracellular Ca2+. It is concluded that, after dissociation of 5HT from the platelet 5HT2-receptor, 5HT-induced responses rapidly resensitize. Because of its short duration and the parallelism in recovery between the different 'down-stream phospholipase C' intracellular transduction signals, it is considered that desensitization arises from a reversible change in the transduction mechanism at a step up to or including the activation of phospholipase C. Neither desensitization nor resensitization to 5HT is dependent on the presence of extracellular Ca2+.
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PMID:Desensitization and resensitization of human platelets to 5-hydroxytryptamine at the level of signal transduction. 774 8

The relationship between platelet aggregation, calpain activation, PKC activities and the secretory response have been examined in PMA-and ionomycin-stimulated platelets. Co-addition of PMA and ionomycin resulted in a maximal synergistic secretion of [14C]5-hydroxytryptamine ([14C]5-HT) from platelet dense granules. However, prior addition of PMA for 5 or 10 min resulted in a reduction of this secretory response. Inclusion of either RGDS (to inhibit platelet aggregation) or E64-d (to inhibit calpain activity) resulted in full restoration of the secretory response. In experiments to determine the activity status of PKC, PMA was found to induce a loss in cytosolic and total PKC activity without an increase in membrane-associated activities during this time period. Inhibition of either platelet aggregation or calpain activity resulted in preservation of total and cytosolic activities with a measurable increase in membrane translocated activity. PMA-induced phosphorylation of a number of PKC substrates was measured in 32P-labelled platelets. PMA induced potent phosphorylation of the 45 and 20 kDa species and also proteins of the molecular masses 66, 80, 97 and 119 kDa. Phosphorylation was maximal at either 1 or 2 min after which dephosphorylation occurred. Inclusion of either RGDS or E64-d resulted in a reduction of the dephosphorylation rates, and sustained phosphorylation of the 66, 80, 97 and 119 kDa proteins. These studies suggest that the activity status of PKC is an important factor in the level of secretion obtained and that platelet aggregation is involved in calpain-initiated down-regulation of PKC.
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PMID:Calpain-induced down-regulation of protein kinase C inhibits dense-granule secretion in human platelets. Inhibition of platelet aggregation or calpain activity preserves protein kinase C and restores full secretion. 780 7

The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, the newest subtype of the 5-HT2 receptor family to be cloned. Although the 5-HT2A and 5-HT2C receptor subtypes couple to phosphatidylinositol hydrolysis, such a coupling has not been established for the 5-HT2B receptor in tissues. Thus, the purpose of this study was to characterize further the signal transduction mechanism of the 5-HT2B receptor in rat stomach fundus. Nitrendipine (1 microM) inhibited the maximal contraction to 5-HT (1 microM) by approximately 50%. Removal of extracellular calcium did not inhibit 5-HT contraction to a greater extent than that produced by nitrendipine, indicating that calcium influx through voltage-dependent calcium channels was predominantly responsible for the dependence of the 5-HT contraction on extracellular calcium. Depletion of both extracellular calcium and intracellular calcium stores abolished 5-HT contraction. Ryanodine (30 microM), a compound which inhibits calcium release from intracellular stores, significantly inhibited the maximal contraction to carbamylcholine (3 microM). In contrast, ryanodine (30 microM) did not inhibit the maximal contraction to 5-HT (1 microM) in the absence of nitrendipine. However, ryanodine (30 microM) did significantly inhibit the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due in part to calcium release from a ryanodine-sensitive store. Bisindolylmaleimide (5 microM), a specific inhibitor of protein kinase C (PKC), inhibited 5-HT contraction in either the absence or presence of nitrendipine, suggesting that activation of PKC is also involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C. 781 26

1. The involvement of protein kinase C (PKC) in constriction of small bronchioles has never been investigated. In this study we have examined the effects of the specific PKC inhibitors Ro31-8220 and Ro31-7549 and the non-specific inhibitor H7 on carbachol-, 5-hydroxytryptamine (5-HT)- and 4 beta-phorbol dibutyrate (4 beta-PDBu)-induced contractions in large and small bronchioles. 2. The study was performed on isolated bronchioles of the rat with internal diameters of 574 microns +/- 11 (small, n = 128), and 1475 microns +/- 32 (large, n = 93), using a Mulvaney-Halpen small vessel myograph. 3. In these preparations 4 beta-PDBu had no effect if added on its own. However, after precontracting with 30 mM K+, 0.5 microM 4 beta-PDBu caused a contractile response of 110.4 +/- 7.0% TK (TK = maximum response to 75 mM K+ in small and 69.3 +/- 6.5% TK in large bronchioles. Ro31-8220, Ro31-7549 and H7 all showed concentration-dependent inhibition of this response. 4. In small bronchioles 10 microM Ro31-8220 shifted both the carbachol and 5-HT concentration-response curves to the right, and reduced the maximum response. In contrast, 10 microM Ro31-8220 had no significant effect on the EC50 to carbachol of larger bronchioles, although the maximum response was reduced, and had no significant effect on the 5-HT concentration-response curve. 200 microM H7 shifted the carbachol concentration--response curve to the right as well as reducing the maximal response in both small and large bronchioles. 5 Large bronchioles exhibited a greater rate of decay of carbachol-induced contraction than did small bronchioles. Pretreatment with Ro31-8220 accelerated the rate of decay.6 Pretreatment with 10 JM Ro3l-8220 caused a small reduction in the response to 75 mM K+ in both small and large bronchioles (small: to 87.8 +/- 3.0% TK; large: to 94.1 +/- 0.8% TK). H7 at 200 JM caused a much larger reduction in both preparations (small: to 75.1 +/- 3.0% TK); large: to 82.7 +/- 0.6% TK).7 Small bronchioles were more sensitive than larger bronchioles to agonists and phorbol ester. The protein kinase inhibitor Ro31-8220 could reduce agonist-induced constriction in small and large bronchioles,as well as reducing or abolishing phorbol ester-induced contractions. Small bronchioles were more sensitive than large bronchioles to Ro31-8220. These results suggest that there is a significant PKC involvement in constriction of bronchioles to carbachol and 5-HT, and that the proportion of the contractile response that can be attributed to PKC is greater in smaller than larger bronchioles.
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PMID:Differences in sensitivity to the specific protein kinase C inhibitor Ro31-8220 between small and large bronchioles of the rat. 788 78

The objective of this study was to analyze the effect of chronic treatment of rabbits for 4, 8 and 12 weeks with the anabolic steroid, nandrolone, on the contractile responses induced by different agents in segments of thoracic aorta and mesenteric and femoral arteries. In the three types of arteries, the contractions elicited by noradrenaline, 5-hydroxytryptamine and angiotensin II were increased by endothelium removal. The treatment reduced the contractions elicited by the three agents (mainly those caused by 5-hydroxytryptamine) in aorta, and only those caused by 5-hydroxytryptamine in mesenteric arteries. Ca(2+)-free medium containing 0.1 mM ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) reduced the responses elicited by 1 microM noradrenaline, 10 microM 5-hydroxytryptamine and 0.1 microM angiotensin II in aorta segments from control rabbits. Addition of CaCl2 to this medium restored the initial responses elicited by the three agents in normal medium, both in arteries from control and treated rabbits. In aorta, the contractions elicited by phorbol 12,13-dibutyrate (PDB), an activator of protein kinase C, were reduced by the treatment. Staurosporine, an inhibitor of protein kinase C, reduced the responses evoked by PDB. Likewise, the contractions caused by noradrenaline, 5-hydroxytryptamine and especially by angiotensin II were also reduced by staurosporine. These results suggest that the thoracic aorta is the most affected by the treatment, and that the reduction of contractile responses appears to be due to changes in protein kinase C activity and/or in a mechanism situated beyond protein kinase C activation.
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PMID:Treatment with the anabolic steroid, nandrolone, reduces vasoconstrictor responses in rabbit arteries. 792 88

The cDNAs for human 5-hydroxytryptamine (5-HT)2C and 5-HT2A receptors were stably transfected separately into parent Chinese hamster ovary cells, and cell lines in which levels of transfected receptor protein expression and accumulation of inositol phosphates in response to 5-HT were comparable were chosen for study. The effect of activation of these receptors on 5-HT1B-like receptor-mediated responsiveness (i.e., inhibition of forskolin-stimulated cAMP accumulation) was studied. Activation of 5-HT2C receptors with 5-HT (0.1-100 microM) abolished the 5-HT1B-like response, which returned when 5-HT2C receptors were blocked with mesulergine (1 microM). Furthermore, the maximal response to 5-carboxytryptamine was reduced in a concentration-dependent manner by the 5-HT2A/5-HT2C-selective partial agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. In contrast, activation of 5-HT2A receptors with either 5-HT or (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane did not alter the 5-HT1B-like response. The reduction of 5-HT1B-like responsiveness produced by 5-HT2C receptor activation was independent of protein kinase C activation and increases in the intracellular calcium concentration. Although 5-HT2A and 5-HT2C receptors are strikingly similar in structure and pharmacology, and the signal transduction systems coupled to these receptors have been thought to be similar, if not identical, these data provide the first evidence for fundamental differences in the signal transduction systems of these 5-HT2 receptor subtypes.
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PMID:Signal transduction differences between 5-hydroxytryptamine type 2A and type 2C receptor systems. 793 28

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