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)

Histamine H1 receptor-mediated production of cGMP in guinea-pig lung tissue becomes rapidly desensitized after previous exposure to histamine. This desensitization is clearly concentration dependent and appears to be homologous. Responses to histamine are also inhibited by previous treatment with phorbol 12,13-dibutyrate. Yet, the time course of the inhibition is considerably slower and the maximal inhibition is significantly less compared to receptor desensitization. Moreover, the effects of the phorbol ester are not confined to H1 receptor responses. Since the effects of receptor desensitization are also not prevented by several protein kinase C inhibitors, the development of homologous H1 receptor desensitization is not dependent upon protein kinase C activation, but is caused by a yet unidentified mechanism.
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PMID:Desensitization of histamine H1 receptor-mediated cyclic GMP production in guinea-pig lung. 131 39

The regulation of histamine-stimulated phosphoinositide turnover by histamine and phorbol esters was examined in intact DDT1 MF-2 cells grown in suspension culture. Histamine increased the incorporation of 32P into phosphatidylinositol (PI) in these cells, and this stimulation was inhibited by the H1 antagonist diphenhydramine but not by the H2 antagonist cimetidine. Pretreatment of cells with histamine or with phorbol 12-myristate 13-acetate (PMA) or other activators of protein kinase C induced a marked decrease in the subsequent stimulation by histamine. PMA, but not histamine, also decreased the ability of epinephrine to stimulate PI labelling through alpha 1-adrenoceptors. Thus, histamine appears to induce homologous desensitization of histamine H1 receptor-mediated PI turnover, whereas direct activation of protein kinase C in the absence of receptor occupancy by agonist induces nonspecific heterologous desensitization of both histamine H1- and alpha 1-adrenoceptor-mediated responses.
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PMID:Regulation of histamine H1 receptor-mediated phosphoinositide hydrolysis by histamine and phorbol esters in DDT1 MF-2 cells. 215 11

GT1-7 cells, a clonal line derived from specific tumours of gonadotropin-releasing hormone-secreting neurons from mouse hypothalamus, were used as a model system to investigate the cellular mechanisms underlying the histamine H1 receptor-mediated desensitisation. GT1-7 cells contain H1 receptors, acute stimulation of which leads to the desensitisation of histamine-mediated calcium mobilisation and is manifest as a concurrent reduction in both the magnitude of the calcium transient and of the sustained phase. Acute pretreatment of the cells with the phorbol ester, phorbol 12-myristate 13-acetate, can also ablate the histamine-stimulated calcium mobilisation. In addition, acute H1-receptor stimulation and acute phorbol ester treatment result in the attenuation of histamine-mediated inositol phosphate production. Receptor desensitisation resulting from acute stimulation with histamine is not affected by inhibiting protein kinase C (PKC) activity with Ro 31-7549 or staurosporine. In contrast, the desensitisation of H1-receptor responses induced by direct activation of protein kinase C is preventable by PKC inhibitors. Thus, these results imply that a PKC-dependent mechanism and PKC-independent mechanism are involved in the H1-receptor desensitisation cascade in GT1-7 cells and do not support the involvement of PKC in the receptor-mediated desensitisation of H1 receptor-stimulated calcium and inositol phosphate responses.
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PMID:Receptor-mediated desensitisation of histamine H1 receptor-stimulated inositol phosphate production and calcium mobilisation in GT1-7 neuronal cells is independent of protein kinase C. 779 Aug 57

A cDNA encoding a guinea pig histamine H1 receptor was stably expressed in Chinese hamster ovary (CHO) cells. In one resulting clone, named CHO(H1), the H1 receptor was found to be coupled to several major signal transduction pathways. In each case the involvement of a Gi/Go protein with pertussis toxin (PTX) was assessed, as well as the influence of extracellular Ca2+ and of protein kinase C activation by phorbol 12-myristate 13-acetate (PMA). Histamine induced, in a PTX- and PMA-insensitive manner, a biphasic increase in the intracellular Ca2+ level of which only the second sustained phase was dependent on the extracellular Ca2+ level. Histamine also caused a threefold elevation of inositol phosphate production, which was PTX-insensitive, but slightly inhibited by PMA and reduced by 75% in the absence of extracellular Ca2+. Histamine also caused a massive release of arachidonic acid, which occurred in a Ca(2+)- and PMA-sensitive manner, probably through the activation of a cytosolic phospholipase A2, which partly involves coupling to a PTX-sensitive G protein. In comparison, in HeLa cells endowed with a native H1 receptor, the histamine-induced arachidonic acid release was also Ca(2+)- and PMA-sensitive, but totally PTX-insensitive. Finally, in CHO(H1) cells, histamine in very low concentrations potentiated the cyclic AMP accumulation induced by forskolin. This response appeared to be insensitive to PTX, extracellular Ca2+, and PMA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guinea pig histamine H1 receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. 829 14

[3H]Inositol phosphate responses to histamine and a range of other agonists were studied in cultured human tracheal smooth muscle cells. Histamine (EC50 6.5 microM), bradykinin (EC50 9.7 nM), carbachol (EC50 10 microM), substance P and NaF all produced concentration dependent [3H]inositol phosphate formation in these cells. The response to histamine was inhibited by mepyramine (KA 4.3 x 10(9) M-1), indicating the involvement of the histamine H1 receptor in this response. The inositol phosphate response to histamine was apparently desensitized following prolonged agonist exposure. The response to histamine was inhibited by phorbol dibutyrate (IC50 6 nM), and this inhibitory effect was reversed by staurosporine (150 nM). Isoprenaline (1 microM), rolipram (0.1-100 microM) and 3-isobutyl-1-methylxanthine (0.1 mM) all produced small inhibitory effects upon histamine induced inositol phosphate formation. These results demonstrate that cultured human tracheal smooth muscle cells express histamine H1 receptors coupled to phosphoinositidase C and suggest that the inositol phosphate response induced by stimulation of this receptor subtype is inhibited by activation of protein kinase C and, to a lesser extent, by elevation of cell cyclic AMP content.
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PMID:Control of histamine induced inositol phospholipid hydrolysis in cultured human tracheal smooth muscle cells. 839 92

1. The human H1 receptor gene expressed in Chinese hamster ovary cells (CHOhumH1) encodes a classical histamine H1 receptor with a pharmacology similar to that of the H1 receptor found in guinea-pig cerebellum and the endogenously expressed human H1 receptor in 1321N1 astrocytoma cells as determined by [3H]-mepyramine binding studies. 2. In CHOhumH1 cells, histamine induced a concentration-dependent rise in inositol phosphates (EC50 2.23 +/- 0.97 microM) and a rapid increase of [Ca2+]i, followed by a sustained increase of [Ca2+]i upon addition of 100 microM histamine. 3. Short-term exposure of CHOhumH1 cells to histamine (100 microM) resulted in a decrease of subsequent histamine-induced Ca2+ responses. The histamine-induced desensitization appeared to be heterologous as the ATP-induced Ca2+ response was also found to be affected. 4. The process of heterologous histamine-induced desensitization of the Ca2+ response in CHOhumH1 cells can be ascribed to an alteration at the level of the intracellular Ca2+ pool, as the Ca2+ response of caffeine (10 mM), which releases Ca2+ from intracellular Ca2+ stores was also attenuated upon short-term histamine exposure. 5. In CHOhumH1 cells the PKC activator, PMA, was found to inhibit the histamine (100 microM)-induced Ca2+ response concentration-dependently (IC50 0.2 +/- 0.03 microM) as well as the ATP (100 microM)-induced Ca2+ response. However, this inhibition was only partial and less effective than histamine-pretreatment. Moreover, in CHOhumH1 cells PKC downregulation induced by long-term exposure to PMA (1 microM) did not affect the histamine-induced desensitization nor did pretreatment with the specific PKC inhibitor Ro-31-8220 (10 microM), indicating that in CHOhumH1 cells PKC is probably not involved in the heterologous desensitization. 6. Long-term treatment of CHOhumH1 cells with histamine or other H1 agonists resulted in a time- and concentration-dependent decrease in the number of H1 receptor binding sites (maximal reduction: 47 +/- 5%). 7. Long-term exposure of CHOhumH1 cells to ATP or PMA did not affect H1 receptor density. 8. Both histamine (100 microM)- and ATP (100 microM)-induced Ca2+ responses were affected upon long-term exposure of cells to histamine (100 microM), which might be explained by an alteration at a level distant from the receptor. 9. These results show that in CHOhumH1 cells the human histamine H1 receptor is susceptible to short-term and long-term receptor regulation in which PKC does not seem to play a role. The CHOhumH1 cells therefore provide an excellent model system for studying the mechanism(s) of PKC-independent H1 receptor regulation.
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PMID:Regulation of the human histamine H1 receptor stably expressed in Chinese hamster ovary cells. 888 99

1. The effects of the specific protein kinase C (PKC) inhibitor, GF109203X, were measured on the cytoplasmic Ca2+ concentration ([Ca2+]i), and on histamine H1 receptor- and thapsigargin-mediated increases in [Ca2+]i in DDT1 MF-2 smooth muscle cells. 2. After pretreatment of cells with GF109203X (5 microM, 45 min), the histamine (100 microM)-induced initial rise in [Ca2+]i, representing Ca2+ mobilization from internal stores, was inhibited (by 59 +/- 7%). The slowly declining phase of the histamine induced Ca2+ response, reflecting Ca2+ entry, was enhanced (83 +/- 26%) in the presence of the PKC inhibitor. 3. The histamine induced release of Ca2+ from internal stores, measured after blocking Ca2+ entry with LaCl3 was inhibited by GF109203X in a concentration-dependent manner (IC50: 3.1 +/- 1.1 microM). 4. Histamine-induced formation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) was not changed in the presence of GF109203X. 5. The PKC activating phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), strongly reduced histamine-induced Ins(1,4,5)P3 formation (58 +/- 16%). This effect was reversed by GF109203X (5 microM). Furthermore, PMA diminished histamine evoked Ca2+ release (50 +/- 6%) and blocked Ca2+ entry completely. 6. The rise in [Ca2+]i caused by blocking endoplasmic reticulum Ca2(+)-ATPase with thapsigargin (1 microM), was strongly reduced (57 +/- 3%) after pretreatment of cells with GF109203X. Downregulation of PKC by long-term pretreatment of cells with PMA (1 microM, 48 h) did not abolish this effect of GF109203X (48 +/- 3% inhibition). 7. In permeabilized DDT, MF-2 cells preloaded with 45Ca2+ in the presence of GF109203X, the amount of 45Ca2+ released by Ins(1,4,5)P3 (10 microM) was markedly reduced (42 +/- 9%). GF109203X did not release Ca2+ itself and did not impair Ins(1,4,5)P3 receptor function. 8. Uptake of 45Ca2+ by intact cells, representing Ca2+ entry, was enhanced by GF109203X (65 +/- 11%), by histamine (24 +/- 6%) and also by thapsigargin (121 +/- 10%). The GF109203X- and the thapsigargin-induced uptake of 45Ca2+ were not additive. 9. These data suggest that GF109203X reduces the filling-state of intracellular Ins(1,4,5)P3 sensitive Ca2+ stores by inhibiting the Ca2+ uptake into these stores, thereby promoting store-dependent (capacitive) Ca2+ entry.
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PMID:The effect of the PKC inhibitor GF109203X on the release of Ca2+ from internal stores and Ca2+ entry in DDT1 MF-2 cells. 890 48

The secretory responses in rat adrenal chromaffin cells to histamine H1 receptor stimulation desensitize during repetitive stimulation. The rate of development of this desensitization was slowed by Ro 31-8220, a protein kinase C (PKC) inhibitor. Ro 31-8220 also reversed part of the desensitization which had been induced by earlier histamine stimulation. Phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C, inhibited histamine-evoked catecholamine (CA) secretion almost completely. The inhibitory effect of PDBu on the H1-receptor-mediated secretory response was antagonized by Ro 31-8220. Histamine induced [Ca2+]i increases due to Ca2+ entry and Ca2+ release from intracellular Ca2+ stores in fura-2-loaded adrenal medullary cells. These [Ca2+]i increases were abolished in PDBu-treated cells. These results suggest that the activation of PKC following histamine H1 receptor stimulation plays a significant role in the process of homologous desensitization of histamine-evoked secretory responses in rat chromaffin cells, through modulation by PKC of H1 receptors and/or GTP-binding proteins coupled with H1 receptors.
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PMID:Involvement of protein kinase C in homologous desensitization of histamine-evoked secretory responses in rat chromaffin cells. 926 56

We have investigated the role of protein kinase C (PKC) in the desensitization of histamine H1-receptors and in the expression of the histamine H1-receptor gene in airway smooth muscle. Prolonged 4beta-phorbol 12,13 dibutyrate (PDBu) pretreatment (4 h, 100 nM-1 microM) of bovine trachealis caused a concentration-dependent loss of contraction in response to histamine H1-receptor stimulation, which was associated with a concentration-dependent decrease in histamine-induced total [3H]-inositol phosphates accumulation. In contrast, the responses to sodium fluoride, a direct G-protein activator, were unalterd by PDBu (100-300 nM) pre-incubation and only slightly reduced following incubation with 1 microM PDBu. A selective PKC inhibitor, GF 109203X, partially blocked the PDBu (1 microM)-induced desensitization and completely blocked the effect of 100 nM PDBu, confirming the involvement of PKC. Binding experiments using [3H]-pyrilamine revealed a class of high-affinity binding sites within the range for the histamine H1 receptor in airway smooth muscle. PDBu (1 microM) pretreatment for 4 h did not change the number of histamine H1 receptors. PDBu (1 microM) exposure caused a time-dependent reduction in the steady-state levels of histamine H1-receptor mRNA, which was inhibited by pre-incubation with GF 109203X and by cycloheximide, a protein synthesis inhibitor. Nuclear run-on assays revealed a 50% reduction in the rate of histamine H1-receptor gene transcription after 17 h PDBu pretreatment, whereas mRNA stability was not affected by PDBu pretreatment (17 h). In conclusion, we have shown a PKC-mediated desensitization of the histamine H1-receptor in BTSM and a transcriptional down-regulation of the histamine H1-receptor gene expression, which requires new protein synthesis.
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PMID:Desensitization of the histamine H1-receptor and transcriptional down-regulation of histamine H1-receptor gene expression in bovine tracheal smooth muscle. 988 76

The histamine H1 receptor (H1R)-mediated signaling cascade is inhibited by phorbol ester-induced protein kinase C (PKC) activation. Cloning studies of the H1Rs have shown that several potential PKC phosphorylation sites are located in the third intracellular loop of H1R. To elucidate the molecular mechanism of PKC-mediated desensitization, we identified amino acid residues that are involved in the desensitization of the H1R. Two amino acid residues (Ser396, Ser398) were determined to be PKC phosphorylation sites by in vitro phosphorylation studies using a series of synthetic peptides. Treatment with phorbol ester decreased histamine-induced accumulation of inositol phosphates in Chinese hamster ovary cells expressing the H1R with a rightward shift in the EC50 value, which implies the uncoupling of the receptor from the G protein. Site-directed mutagenesis studies showed that substitution of alanine for Ser398 but not for Ser396 markedly attenuated the effect of phorbol ester, which suggests that the Ser398 residue was primarily involved in PKC-mediated desensitization.
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PMID:Identification of protein kinase C phosphorylation sites involved in phorbol ester-induced desensitization of the histamine H1 receptor. 1010 Oct 32


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