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)

Bombesin-like peptides have been recently shown to regulate immune functions. In the present work, we have studied their action as chemoattractants for murine peritoneal macrophages and lymphocytes. The results showed a significant increase in the number of cells that migrate when they are exposed to a gradient of bombesin, gastrin-releasing peptide (GRP) or neuromedin C (from 10(-8) to 10(-12) M). The most effective of the three neuropeptides studied was GRP, even more than formyl-Met-Leu-Phe peptide (FMLP), an established leukocyte chemoattractant. GRP action was mediated through specific cell receptors as it was significantly reduced in presence of a competitive and specific bombesin receptor antagonist. In the presence of retinal, a protein kinase C (PKC) inhibitor, the chemoattractant capacity of GRP was considerably reduced. In order to investigate further the mechanism of action involved in the GRP effect, we measured PKC activity. Peritoneal cells incubated with GRP experimented an increase in PKC activity to the same extent of that produced by the PKC activator phorbol myristate acetate (PMA). These data prove that bombesin-like peptides are potent chemoattractants for murine peritoneal macrophages and lymphocytes, and that their action is at least in part mediated through PKC activation.
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PMID:Chemoattractant capacity of bombesin, gastrin-releasing peptide and neuromedin C is mediated through PKC activation in murine peritoneal leukocytes. 814 Feb 72

Bombesin and the two mammalian bombesin-related peptides, gastrin-releasing peptide (GRP) and neuromedin C, at physiological concentrations ranging from 10(-11) M to 10(-9) M have been shown in this study to significantly stimulate in vitro the antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) activities in BALB/c mouse leukocytes from axillary nodes, spleen and thymus. The three neuropeptides studied induced no change in interleukin-2 production. In addition, these neuropeptides induced in leukocytes from axillary nodes a rapid, transient and significant decrease of intracellular cyclic AMP at 30 s, but a significant transient increase of inositol 1,4,5-trisphosphate levels at 30 and 60 s and a stimulation of protein kinase C activity in membrane fractions after 5 min incubation. These results suggest that inositol phospholipid signalling and cAMP messenger systems are involved in the increase of NK and ADCC activities when leukocytes are incubated in the presence of bombesin, GRP or neuromedin C.
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PMID:Stimulation of natural killer and antibody-dependent cellular cytotoxicity activities in mouse leukocytes by bombesin, gastrin-releasing peptide and neuromedin C: involvement of cyclic AMP, inositol 1,4,5-trisphosphate and protein kinase C. 822 12

Gastrin-releasing peptide (GRP) and bombesin apparently enhance the rate of secretion of surfactant lipids from cultured fetal rat type II pneumocytes. This effect, evident within 1h of addition of the peptide, is concentration-dependent, with a maximal response at 3.0 nM. When the effect of GRP was assessed in comparison with other known secretagogues, it was found that, whereas GRP and isoproterenol were additive in their effect, there was no response to GRP in the presence of saturating concentrations of A23187 or phorbol 12-myristate 13-acetate. This suggests that the secretory response to GRP is via activation of Ca2+/calmodulin-dependent protein kinase and/or protein kinase C and is independent of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. This conclusion is supported by the observation that the GRP-induced secretion is inhibited by calphostin C, an inhibitor of protein kinase C, but not by H-89, an inhibitor of cAMP-dependent protein kinase. The fact that GRP regulates surfactant secretion from type II pneumocytes suggests that it and/or related peptides may play a significant role in the physiological maturation of the lung.
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PMID:Stimulation of surfactant lipid secretion from fetal type II pneumocytes by gastrin-releasing peptide. 863 24

Mammalian bombesin-like peptides gastrin-releasing peptide (GRP) and neuromedin B (NMB) are regulatory neuropeptides involved in numerous physiologic processes, and have been implicated as autocrine and/or paracrine growth factors in human lung carcinoma. Three structurally and pharmacologically distinct bombesin receptor subtypes have been isolated and characterized: the gastrin releasing peptide receptor (GRP-R), the neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). The three receptors are structurally related, sharing about 50% amino acid identity. They are members of the G-protein coupled receptor superfamily with a seven predicted transmembrane segment topology characteristic of receptors in this family. The signal transduction pathway for GRP-R and NMB-R involves coupling to a pertussis-toxin insensitive G-protein, activation of phospholipase C (PLC), generation of inositol trisphosphate (IP3), release of intracellular calcium, and activation of protein kinase C. While all three bombesin receptors are activated by bombesin agonists, GRP-R, NMB-R, and BRS-3 have very different affinities for the mammalian bombesin-like peptides GRP and NMB, as well as bombesin receptor antagonists. The three bombesin receptor subtypes are expressed in an overlapping subset of human lung carcinoma cell lines. Any therapeutic strategy based on modulation of bombesin growth responses in human lung carcinoma would be well served to take into account the pharmacologic heterogeneity of the relevant receptors.
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PMID:Bombesin receptor structure and expression in human lung carcinoma cell lines. 880 6

Gastrin-releasing peptide and other bombesin-like peptides stimulate secretion, cell proliferation, and smooth muscle contraction via a family of G protein-coupled receptors that activate phospholipase C. Second messenger formation by one of these receptors, called BR1, is rapidly desensitized after treatment of cells with either agonists or the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA). To determine whether receptor phosphorylation was involved in BR1 desensitization, we generated antibodies to a peptide corresponding to a unique sequence within the COOH terminus of this receptor. One antibody (BR1-517) immunoprecipitated 60% of the solubilized [125I-Tyr4]bombesin/receptor complex prepared from either Swiss 3T3 fibroblasts or CHO-K1 cells transfected to express high levels of mouse BR1 (CHO-mBR1). Furthermore, immunoprecipitation of photoaffinity-labeled receptors yielded the expected 87-kDa radiolabeled band on gel electrophoresis. Phosphorylation of this immunoprecipitated receptor protein was markedly stimulated when [32P]orthophosphate-labeled Swiss 3T3 cells or CHO-mBR1 cells were treated with 100 nM bombesin for 5 min. 32PO4 incorporation into immunoprecipitated receptor was detectable after 2 min and maximal after 15 min of bombesin treatment. Phosphoamino acid analysis showed 32P labeling of serine and theonine but not tyrosine residues. Pretreatment of CHO-mBR1 cells with 100 nM TPA for 30 min also desensitized bombesin stimulation of inositol-1,4,5-trisphosphate formation. However, TPA did not increase 32PO4 incorporation into the immunoprecipitated receptor, although protein kinase C inhibition potentiated bombesin-induced receptor phosphorylation. Subsequent studies showed that TPA did stimulate receptor phosphorylation, but the antibody did not recognize this phosphorylated state of the receptor. Thus, TPA decreased the efficiency of receptor immunoprecipitation, and subsequent incubation of receptor with alkaline phosphatase reversed this TPA inhibition. The differential specificity of the antibody for various phosphorylated forms of BR1 demonstrates that agonist-induced and TPA-induced phosphorylations of the receptor occur at distinct sites.
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PMID:Agonist binding and protein kinase C activation stimulate phosphorylation of the gastrin-releasing peptide receptor at distinct sites. 886 15

The mechanism by which gastrin-releasing peptide (GRP) increases cytoplasmic calcium [Ca2+]ic was studied in insulin-producing HIT-T15-cells. At zero glucose, GRP (100 nM) rapidly increased [Ca2+]ic in the presence and absence of extracellular Ca2+. The effect was potentiated by glucose, impaired by the inhibitor of microsomal Ca(2+)-ATPase, thapsigargin, and abolished by the inhibitor of phospholipase C U73122. In contrast, the inhibitor of Ca2+ induced Ca2+ release, ryanodine, was without effect. Furthermore, the GRP-induced increase in [Ca2+]ic was potentiated by forskolin and impaired by activation of protein kinase C (PKC) by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Based on these results, we conclude: 1) that GRP mobilizes Ca2+ from a thapsigargin-sensitive intracellular Ca2+ pool through activation of phospholipase C, and 2) that the GRP-induced mobilization of Ca2+ is potentiated by cyclic AMP.
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PMID:Gastrin-releasing peptide mobilizes calcium from intracellular stores in HIT-T15 cells. 889 8

Recent studies show that tyrosine phosphorylation by a number of neuropeptides may be an important intracellular pathway in mediating changes in cell function, particularly related to growth. Neuromedin B (NMB), a mammalian bombesin related peptide, functions through a distinct receptor, the neuromedin B receptor (NMB-R), of which little is known about its cellular basis of action. In the present study we explored the ability of NMB-R activation to cause tyrosine phosphorylation of focal adhesion kinase (p125(FAK)), an important substrate for tyrosine phosphorylation by other neuropeptides. NMB caused rapid increases in p125(FAK) phosphorylation which reached maximum at 2 min in both rat C6 glioblastoma cells which possess native NMB-Rs and rat neuromedin B receptor (rNMR-R) transfected BALB 3T3 cells. NMB had a half-maximal effect was at 0.4 nM and was 30-fold more potent than gastrin-releasing peptide (GRP). The stoichiometric relationships between increased p125(FAK) tyrosine phosphorylation and other cellular processes was similar in both C6 cells and rNMB-R transfected cells. TPA (1 microM) caused 45% and the calcium ionophore, A23187, 11% of maximal tyrosine phosphorylation of p125(FAK) seen with NMB. A23187 potentiated the effect of TPA. Pretreatment with the selective PKC inhibitor, GF109203X, inhibited TPA-induced p125(FAK) tyrosine phosphorylation, but it had no effect on the NMB stimulation. Pretreatment with thapsigargin completely inhibited NMB-stimulated increases in [Ca2+]i, but had no effect on NMB-stimulation of p125(FAK) phosphorylation either alone or with GF109203X. The tyrosine kinase inhibitor, tyrphostin A25, inhibited NMB-induced phosphorylation of p125(FAK) by 52%. However, tyrphostin A25 did not inhibit NMB-stimulated increases in [3H]inositol phosphates. Cytochalasin D, an agent which disrupts actin microfilaments, inhibited BN- and TPA-induced tyrosine phosphorylation of p125(FAK) completely. In contrast, colchicine, an agent which disrupts microtubules, had no effect. Pretreatment with Clostridium botulinum C3 exoenzyme which inactivates the small GTP-binding protein rho p21, also inhibited tyrosine phosphorylation of p125(FAK) by 55%. These results demonstrate that activation of NMB-R can cause rapid tyrosine phosphorylation of p125(FAK). NMB-induced tyrosine phosphorylation of p125(FAK) is independent of NMB-induced changes in [Ca2+]i or PKC. The integrity of the actin cytoskeleton but not of microtubules is necessary for NMB-stimulated phosphorylation of p125(FAK). The ras-related small GTP-binding protein rho p21 is at least partially involved in mediating NMB-induced tyrosine phosphorylation of p125(FAK). These results suggest that similar to some other neuropeptides, activation of this pathway may be an important mechanism in mediating cellular changes by this receptor such as growth.
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PMID:Neuromedin B receptor activation causes tyrosine phosphorylation of p125FAK by a phospholipase C independent mechanism which requires p21rho and integrity of the actin cytoskeleton. 940 68

Prostaglandins, produced in response to mitogens and cytokines, are potent modulators of gastrointestinal physiology and pathophysiology. We investigated modulation of Prostaglandin synthase 2 (PGS-2) expression by the gastrin-releasing peptide (GRP) receptor in Swiss 3T3 cells. PGS-2 mRNA expression in Swiss 3T3 cells was determined by Northern blot analysis. PGS-2 protein expression in Swiss 3T3 cells was measured by Western blot analysis. GRP caused a transient induction of PGS-2 mRNA in Swiss 3T3 cells that resulted in GRP-dependent expression of PGS-2 protein. Transcriptional activation of PGS-2 by GRP was independent of de novo protein synthesis and was not affected by pertussis toxin. Comparison of signaling pathways used by PMA or EGF to those used by GRP showed that PGS-2 induction by GRP increased under conditions that inhibit PKC activity. Dexamethasone, which blocks PMA and EGF induction of PGS-2, also inhibited GRP-induced accumulation of PGS-2 mRNA. These results show that PGS-2 expression in Swiss 3T3 cells is not only controlled by PKC and receptor tyrosine kinase pathways but also by G-protein coupled receptor signaling pathways.
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PMID:Gastrin-releasing peptide-induced expression of prostaglandin synthase-2 in Swiss 3T3 cells. 949 Dec 6

The actions of neuromedin B (NMB), a recently discovered mammalian bombesin-related peptide, are mediated by interacting with a distinct receptor; however, little is known about its cellular basis of action. Recent studies show activation of phospholipase D (PLD) is an important transduction cascade for a number of GI hormones, especially for stimulation of growth and protein sorting. The purpose of the present study was to determine whether activation of the NMB receptor causes activation of PLD and to explore whether this activation was coupled to PLC activation. Rat C6 glioblastoma cells (C6 cells), which contain a low density of native NMB receptors and BALB 3T3 cells stably transfected with rat NMB receptors, were used. NMB caused a 3-fold increase in C6 cells and an 11-fold increase in rNMB-R transfected cells in PLD activity. Increases in PLD activity were rapid and NMB was 100-fold more potent than gastrin-releasing peptide (GRP). NMB caused a half-maximal increase in [Ca2+]i at 0.2 nM, in [3H]IP and PLD at 1 nM, and half-maximal receptor occupation at 1.2 nM. TPA increased PLD dose-dependently with a half-maximal effect at 60 nM. The calcium ionophore A23187 (1 microM) alone did not increase PLD activity but potentiated the effect of TPA. The Ca2+-ATPase inhibitor, thapsigargin, did not affect NMB- or TPA-stimulated PLD activities, although it blocked completely the NMB-induced increase in [Ca2+]i. The PKC inhibitor GF109203X completely abolished TPA-induced PLD activity, however, it only inhibited NMB-induced PLD activity by 20%. The combination of thapsigargin and GF109203X had the same effect as GF109203X alone. These data indicate that NMB receptor activation is coupled to both PLC and PLD. In contrast to a number of other phospholipase C-coupled receptors, NMB receptor stimulated changes in [Ca2+]i do not contribute to PLD activation. Both PKC-dependent and PKC-independent mechanisms are involved in the NMB-stimulated PLD activation with the PKC-independent pathway predominating.
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PMID:Neuromedin B activates phospholipase D through both PKC-dependent and PKC-independent mechanisms. 955 86

Although activation of G protein-coupled inward rectifying K+ (GIRK) channels by Gi/Go-coupled receptors has been shown to be important in postsynaptic inhibition in the central nervous system, there is also evidence to suggest that inhibition of GIRK channels by Gq-coupled receptors is involved in postsynaptic excitation. In the present study we addressed whether the Gq-coupled receptors of the bombesin family can couple to GIRK channels and examined the mechanism by which this process occurs. Different combinations of GIRK channel subunits (Kir3.1, Kir3.2, and Kir3.4) and bombesin receptors (BB1 and BB2) were expressed in Xenopus oocytes. In all combinations tested GIRK currents were reversibly inhibited upon application of the bombesin-related peptides, neuromedin B or gastrin-releasing peptide in a concentration-dependent manner. Incubation of oocytes in the phospholipase C inhibitor U73122 or the protein kinase C (PKC) inhibitors chelerythrine and staurosporine significantly reduced the inhibition of GIRK currents by neuromedin B, whereas the Ca2+ chelator, BAPTA-AM had no effect. The involvement of PKC was further demonstrated by direct inhibition of GIRK currents by the phorbol esters, phorbol-12,13-dibutyrate and phorbol-12-myristate-13-acetate. In contrast, the inactive phorbol ester 4alpha-phorbol and protein kinase A activators, forskolin and 8-bromo cAMP did not inhibit GIRK currents. At the single-channel level, direct activation of PKC using phorbol ester phorbol-12, 13-dibutyrate caused a dramatic reduction in open probability of GIRK channels due to an increase in duration of the interburst interval.
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PMID:Bombesin receptors inhibit G protein-coupled inwardly rectifying K+ channels expressed in Xenopus oocytes through a protein kinase C-dependent pathway. 1034 43


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