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)

The activation of NK1 receptors on U373 MG human astrocytoma cells by substance P (SP) and related tachykinins was accompanied by an increase in taurine release and an accumulation of inositol phosphates. Both of these effects could be inhibited by spantide, a SP receptor antagonist. The relative potency of tachykinins in stimulating 3H-inositol phosphate accumulation correlated very well with their effects in stimulating the release of [3H]-taurine and inhibition 125I-Bolton-Hunter reagent-conjugated SP binding. The effect on [3H]taurine release was mimicked by a protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA). The inactive phorbol ester analogue 4-alpha-phorbol 12,13-didecanoate, however, was without effect. Both SP- and PMA-induced releases of [3H]-taurine were markedly inhibited by staurosporine, a potent PKC inhibitor. Pretreatment of U373 MG cells with 10 microM PMA for 19 h to down-regulate PKC activity also markedly inhibited both SP- and PMA-induced releases of [3H]-taurine. Treatment of cells with 100 nM SP induced a time-dependent translocation of PKC from the cytosolic fraction to the membrane fraction. These findings are consistent with the hypothesis that an activation of NK1 receptors on U373 MG cells results in the release of inositol phosphates and activation of PKC, which in turn may regulate the release of taurine.
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PMID:Tachykinin-stimulated inositol phospholipid hydrolysis and taurine release from human astrocytoma cells. 137 85

The effects on cytosolic Ca2+ concentration of 2-chloroadenosine and [L-Pro9]-substance P, a selective agonist of NK1 receptors, were investigated on astrocytes from embryonic mice in primary culture. Cells responded to [L-Pro9]-substance P with a transitory increase in cytosolic Ca2+ which was of shorter duration when external Ca2+ was removed. A transient response to 2-chloroadenosine alone occurred. When simultaneously applied, [L-Pro9]-substance P and 2-chloroadenosine evoked a prolonged elevation of cytosolic Ca2+ (up to 30 min). This phenomenon was dependent on the presence of extracellular Ca2+, but insensitive to dihydropyridines, La3+, and Co2+, excluding the implication of voltage-operated Ca2+ channels. Arachidonic acid also induced a sustained elevation of cytosolic Ca2+, but did not increase further the response evoked by [L-Pro9]-substance P and 2-chloroadenosine. The activation of protein kinase C by a diacylglycerol analogue mimicked the effect of [L-Pro9]-substance P in potentiating the 2-chloroadenosine-evoked response. Like 2-chloroadenosine, pinacidil, which hyperpolarizes the cells by opening K+ channels, prolonged the elevation of cytosolic Ca2+ concentration induced by [L-Pro9]-substance P. Conversely, depolarization with 50 mM KCl canceled the effects of either pinacidil or 2-chloroadenosine applied with [L-Pro9]-substance P. Pertussis toxin pretreatment suppressed all the effects induced by 2-chloroadenosine.
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PMID:Synergistic regulation of cytosolic Ca2+ concentration in mouse astrocytes by NK1 tachykinin and adenosine agonists. 171 34

The interaction between neurokinin and excitatory amino acid receptors in the spinal cord have been characterised using the neonatal rat spinal cord in vitro preparation. Ventral root (VR) depolarization evoked by N-methyl-D-aspartate (NMDA) and quisqualate was reversibly enhanced in the presence of subthreshold concentrations of neurokinin A (NKA; 1.0-10 nM), but not by substance P (1.0-5.0 nM). When substance P (SP) was replaced by the metabolically stable substance P methyl ester (SPOMe), both NMDA and quisqualate responses were significantly enhanced. VR depolarization evoked by kainate was not altered by any of the neurokinin (NK) receptor agonists. In the presence of the endopeptidase inhibitors, bestatin, captopril and thiorphan (each 1.0 microM), SP significantly enhanced NMDA-evoked responses. The selective NK1 receptor antagonist (+/-) CP96 345 (100 nM) reversibly blocked the enhancement of NMDA-evoked depolarization by SPOMe. Furthermore, MEN10 376 (50 nM), a selective NK2 receptor antagonist blocked the enhancement of NMDA- and quisqualate-evoked depolarization by NKA. The protein kinase C and protein kinase A inhibitor staurosporine (1.0 microM) blocked the enhancement of excitatory amino acid-induced responses by NK-receptor activation. However, whilst NKA-evoked ventral root depolarization was completely abolished in the presence of staurosporine, SPOMe- and SP-induced depolarizations were unaffected. These data show that activation of NK1 or NK2 receptors enhances NMDA- and quisqualate-evoked ventral root depolarization in the neonatal rat spinal cord. The interaction between neurokinin and excitatory amino acid receptors involves protein kinase C activation.
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PMID:Tachykinin induced regulation of excitatory amino acid responses in the rat spinal cord in vitro. 751 61

Human UC11 astrocytoma cells were used to investigate the role of protein kinase C (PKC) and other kinases in neurokinin (NK)1 receptor desensitization. The selective NK1 receptor agonist [Sar9,Met(O2)11]-substance P stimulated a biphasic accumulation of [3H]inositol phosphates ([3H]IPs) in the presence of 10 mM LiCl in cells that had been prelabeled with [3H]inositol. An initial rapid phase of [3H]IP accumulation during the first 1 min was followed by a slower sustained phase for up to 90 min. These results demonstrate that the human NK1 receptor desensitizes rapidly but only partially. The selective PKC inhibitor Ro31-8220 did not prevent rapid NK1 receptor desensitization but after a longer incubation significantly potentiated human NK1 receptor agonist-stimulated accumulation of [3H]IPs. These results suggest that, although PKC does not mediate the process of rapid desensitization, it does have an inhibitory role at later times. This conclusion is supported by studies with staurosporine, phorbol dibutyrate, and the protein phosphatase inhibitor okadaic acid. Studies using AlF4-, an agent that can directly activate G proteins, and Ro31-8220 suggested that PKC can exert inhibitory effects 'downstream' of receptor activation, although immunoprecipitation of the G proteins alpha q/alpha 11 demonstrated that they do not undergo phosphorylation in UC11 cells and are unlikely to be the target of PKC-mediated inhibitory feedback. Delayed inhibitory feedback by PKC may be mediated by phosphorylation of phospholipase C, although an additional site of action on the NK1 receptor cannot be ruled out.
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PMID:Protein kinase C mediates delayed inhibitory feedback regulation of human neurokinin type 1 receptor activation of phospholipase C in UC11 astrocytoma cells. 752 12

1. The mechanisms underlying bradykinin (BK)-mediated contractions in strips of guinea-pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists. 2. Addition of BK and related kinins (0.1 pM-10 microM) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM-1 nM) and low affinity (3 nM-10 microM). The rank order of potency for the first phase (mean EC50, pM) was: BK (1.36) = Hyp3-BK (1.44) = Lys-BK (1.54) > Tyr8-BK (2.72) > Met-Lys-BK (4.30). The rank order of potency for the second phase (mean EC50, nM, at concentration producing 50% of the contraction caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK (60.92) > BK (77.35). The contractile responses (g of tension) to 3 microM of BK (the highest concentration tested) were: Hyp3-BK, 1.76 +/- 0.09; BK, 1.65 +/- 0.12; Lys-BK, 1.45 +/- 0.13; Tyr8-BK, 1.36 +/- 0.15 and Met-Lys-BK, 1.36 +/- 0.15. The selective B1 agonist, des-Arg9-BK, caused only a weak contraction with maximal response (0.21 +/- 0.05 g), which corresponded to approximately 10% of that induced by BK. 3. BK-induced contraction in GPG was inhibited by indomethacin (3 microM) or ibuprofen (30 microM), and was partially reduced by phenidone (30 microM), but was not affected by atropine (1 JM), nicardipine (1 gM),Ca2+-free medium plus EGTA, dazoxiben (30 nM), L-655,240 (10 nM, a selective receptor antagonist ofthromboxane A2), MK-571 (0.1 microM, a selective leukotriene D4 receptor antagonist), tetrodotoxin(0.3microM), CP 96,345 (0.3 microM, a NK1 receptor antagonist), mepyramine (1 microM), glibenclamide (1 microM), H-7(3 microM), staurosporine (100 nM), or phorbol 12-myristate 13-acetate (1 microM). However, BK-induced contractions in GPG maintained in Ca2+-free medium were markedly attenuated by ryanodine (10microM).4. Prostaglandin E2, prostaglandin F2alpha or U46619 (0.1 nM to 100microM), caused concentration-dependent contractions in GPG with mean EC50s of 3.1 microM; 1.7 microM and 0.47 nM and maximal responses of1.36 +/-0.15; 1.32 +/- 0.20 and 0.96 +/- 0.09 g, respectively.5. The selective B2 receptor antagonists, Hoe 140, NPC 17731 and NPC 17761 (0.01 -1 microM), caused concentration-dependent displacements to the right of the contractile concentration-response curve for BK. The selective B1 receptor antagonist, des-Arg9-[Leu8]-BK (1 microM), did not affect BK-induced GPG contraction.6. These data suggest that both high and low affinity BK responses in GPG are mediated by activation of B2 receptors, and that BK-mediated contraction in GPG depends on the release of intracellular Ca2+sources sensitive to ryanodine. In addition, BK-induced contraction in GPG is mediated by release of proinflammatory eicosanoid(s) derived from the cyclo-oxygenase pathway from arachidonic acid metabolism unrelated to thromboxane A2, and seems not to be coupled to activation of a protein kinase C-dependent mechanism.
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PMID:Mechanisms of bradykinin-induced contraction of the guinea-pig gallbladder in vitro. 759 22

The hydroalcoholic extract of Phyllanthus urinaria (Euphorbiaceae), substance P and substance P methyl ester all caused graded contractions in the guinea-pig urinary bladder. Responses to hydroalcoholic extract and substance P were markedly inhibited in calcium-free Krebs solution, this effect being reversed by reintroduction of calcium in the medium. The contraction in response to hydroalcoholic extract was unaffected by atropine, propranolol, prazosin, yohimbine, tetrodotoxin, w-conotoxin, nicardipine, HOE 140, guanethidine, staurosporine, phorbol ester or indomethacin, excluding the involvement of nervous mediated responses, or action via cholinergic, adrenergic, kinins, cyclo-oxygenase metabolites, protein kinase C or activation of L or N-type calcium channels. The selective NK1 tachykinin antagonist (FK 888), but not NK2 (SR 48968) antagonized substance P-induced contraction, but both drugs failed to effect Phyllanthus urinaria-induced contraction. Prolonged desensitization of guinea pig urinary bladder with capsaicin (10 microM) or preincubation of guinea-pig urinary bladder with capsazepine did not affect contraction caused by hydroalcoholic extract. Ruthenium red almost completely abolished capsaicin-induced contraction, but had no effect on hydroalcoholic extract-mediated contraction. Substance P and the hydroalcoholic extract caused marked potentiation of the twitch response in the preparations field stimulated. The facilitatory effect of substance P, but not that of hydroalcoholic extract, was prevented by the NK1 (FK 888), but not by NK2 (SR 48968) antagonist. We concluded that contraction induced by hydroalcoholic extract of Phyllanthus urinaria in the guinea pig urinary bladder involves direct action on smooth muscle and relies on the mobilization of extracellular calcium influx unrelated to activation of L- and N-type calcium channels or activation of protein kinase C mechanisms. In addition contraction caused by the hydroalcoholic extract of Phyllanthus urinaria in guinea-pig urinary bladder does not involve the activation of tachykinin or vanilloid receptors.
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PMID:Analysis of the mechanisms underlying the contractile response induced by the hydroalcoholic extract of Phyllanthus urinaria in the guinea-pig urinary bladder in-vitro. 858 54

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.
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PMID:Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. 867 32

The effect of substance P (SP) on atrial natriuretic peptide (ANP) release was studied in neonatal rat ventricular cardiomyocytes. Incubation of cells with SP led to a marked increase in ANP secretion, a response accompanied by increases in alpha-type protein kinase C (PKC) in the membranous cell fraction and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) formation and a small increase in adenosine 3',5'-cyclic monophosphate (cAMP) production. A role for PKC in SP-induced 6-keto-PGF1 alpha formation and ANP release was apparent insofar as the responses were suppressed by PKC inhibitors and in PKC-downregulated cells. Furthermore, SP-induced 6-keto-PGF1 alpha production was strongly correlated with SP-induced ANP secretion (r = 0.91, P < 0.0001, n = 27), suggesting a role for prostaglandins in SP-mediated ANP release. Supporting this, indomethacin abolished SP-induced ANP release, whereas PGE2, PGF2 alpha, and prostacyclin (PGI2) promoted ANP secretion in this system. Both the profile of SP-induced cAMP production and results obtained with prostaglandin antagonists suggest that a prostanoid FP receptor is at the basis of this response. Finally, both neurokinins A and B induced similar ANP responses, whereas cultured cells were found to contain mRNA transcripts coding for both neurokinin NK1 and NK3 receptor subtypes. Overall, these results suggest that SP induces ANP secretion in neonatal ventricular cardiomyocytes through a PKC- and prostaglandin-dependent signaling pathway.
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PMID:Stimulation of atrial natriuretic peptide release by neurokinins in neonatal rat ventricular cardiomyocytes. 878 Jan 88

Matrix metalloproteinases participate in normal physiologic processes; however, their overproduction has been associated with connective tissue destruction in a variety of pathological states. Migrating basal keratinocytes transiently express collagenase-1 during normal cutaneous reepithelialization. However, the overexpression of both collagenase-1 and stromelysin-1 has been associated with the pathogenesis of chronic nonhealing ulcers. Aberrant expression of metalloproteinases in inflammation is mediated, at least in part, by soluble factors. Since hepatocyte growth factor/scatter factor (HGF/SF) has been reported to promote keratinocyte migration and proliferation, key events in wound repair, and since HGF/SF is produced by dermal fibroblasts and its c-Met receptor is expressed by basal keratinocytes in wounded skin, we have studied the effects of HGF/SF upon keratinocyte metalloproteinase expression. We have found that HGF/SF can stimulate keratinocyte collagenase-1 and stromelysin-1 production in a dose-dependent and matrix-dependent manner. Expression of 92-kDa gelatinase was not affected by HGF/SF. We determined that HGF/SF regulation of collagenase-1 expression is transcriptionally mediated and requires tyrosine kinase and protein kinase C activaties. HGF/NK1, a naturally occurring, truncated form of HGF/SF, also stimulates collagenase-1 production, but much less efficiently than does the parent molecule. However, HGF/NK2, another HGF/SF splice variant, as well as heparin, potently inhibit HGF/SF-induced collagenase-1 synthesis. These results indicate that HGF/SF and its naturally occurring splice variants have diverse biological effects on keratinocytes and suggest an additional mechanism whereby HGF/SF may regulate keratinocyte function during wound repair.
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PMID:Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. 879 21

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4


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