Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation of saliva formation by parotid acinar cells, which comprise the majority of cells in this salivary gland, is initiated by the release of neurotransmitters (acetylcholine, substance P) from parasympathetic nerves. In response to substance P and the muscarinic agonist carbachol, two ligands that activate phospholipase C-linked receptors, which stimulate fluid secretion, PKC delta was phosphorylated on tyrosine residues. The maximal agonist-dependent tyrosine phosphorylation occurred within seconds of the addition of either agonist and then returned rapidly to a smaller increased level. Phorbol ester also caused a rapid increase in tyrosine phosphorylation, which reached a maximal level 5 min after the addition of phorbol 12-myristate 13-acetate. The increase in tyrosine phosphorylation of PKC delta was blocked by tyrosine kinase inhibitors genistein and staurosporine. Ionophore-mediated elevation of [Ca2+]i or activation of the beta-adrenergic receptor, epidermal growth factor receptor, or insulin receptor did not promote the tyrosine phosphorylation of PKC delta. These results indicate that tyrosine phosphorylation plays a role in early signal transduction events promoted by the activation of muscarinic and substance P receptors and suggests that the tyrosine phosphorylation of PKC delta has a role in the activation of fluid secretion by neurotransmitters binding to phospholipase C-linked receptors.
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PMID:Carbachol, substance P, and phorbol ester promote the tyrosine phosphorylation of protein kinase C delta in salivary gland epithelial cells. 753 27

Ligand-induced activation of G protein-coupled receptors is emerging as an important pathway leading to the activation of certain receptors with intrinsic tyrosine kinase activity, such as the epidermal growth factor receptor (EGFR). Substance P (SP) exerts many effects via activation of its G protein-coupled receptor (neurokinin-1, NK-1). SP participates in acute inflammation and activates key proteins involved in mitogenic pathways, such mitogen-activated protein kinases (MAPKs), stimulating DNA synthesis. We tested the hypothesis that SP-induced MAPK activation and DNA synthesis require activation of the EGFR. In U-373 MG cells, which express functional NK-1, SP induced tyrosine phosphorylation of several proteins including EGFR. SP induced formation of an activated EGFR complex containing the adapter proteins SHC and Grb2, but not c-Src. SP activated the MAPK pathway as shown by increased Erk2 kinase activity. SP induced Erk2 activation, and DNA synthesis was inhibited in cells transfected with a dominant negative EGFR plasmid lacking kinase activity, as well as in cells treated with a specific EGFR inhibitor. In addition, pertussis toxin, an inhibitor of Galpha(iota) protein subunits, prevented SP-induced EGFR transactivation and subsequent DNA synthesis. Our results implicate EGFR as an essential regulator in SP/NK-1-induced activation of the MAPK pathway and cell proliferation in U-373 MG cells, and these events are mediated by a pertussis toxin-sensitive Galpha protein. We suggest that this mechanism by which SP controls cell proliferation is an important pathway in tissue restoration and healing.
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PMID:Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells. 1084 86

Substance P analogues including [d-Arg1,d-Phe5,d-Trp7,9,Leu11]substance P (SpD) act as "broad spectrum neuropeptide antagonists" and are potential anticancer agents that inhibit the growth of small cell lung cancer cells in vitro and in vivo. However, their mechanism of action is controversial and not fully understood. Although these compounds block bombesin-induced mitogenesis and signal transduction, they also have agonist activity. The mechanism underlying this agonist activity was examined. SpD binds to the ligand-binding site of the bombesin/gastrin-releasing peptide receptor and blocks the bombesin-stimulated increase in [Ca2+]i within the same concentration range that causes sustained activation of c-Jun N-terminal kinase and extracellular signal-regulated protein kinase (ERK). The activation of c-Jun N-terminal kinase by SpD and bombesin is blocked by dominant negative inhibition of G(alpha12). The ERK activation by SpD is pertussis toxin-sensitive in contrast to ERK activation by bombesin, which is pertussis toxin-insensitive but dependent on epidermal growth factor receptor phosphorylation. SpD does not simply act as a partial agonist but differentially modulates the activation of the G-proteins G(alpha12), G(i), and G(q) compared with bombesin. This unique ability allows the bombesin receptor to couple to G(i) and at the same time block receptor activation of G(q). Our results provide direct evidence that SpD is acting as a "biased agonist" and that this has physiological relevance in small cell lung cancer cells. This validation of the concept of biased agonism has important implications in the development of novel pharmacological agents to dissect receptor-mediated signal transduction and of highly selective drugs to treat human disease.
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PMID:Bombesin and substance P analogues differentially regulate G-protein coupling to the bombesin receptor. Direct evidence for biased agonism. 1132 8

Small cell lung cancers (SCLCs), many non-SCLCs, and other cancers have neuroendocrine features, including paracrineand autocrine growth stimulation by various neuropeptides. Interference with this pathway is an attractive target for novel therapies. We developed a novel bradykinin antagonist dimer, CU201 (B9870), that acts as a "biased agonist" for neuropeptides by blocking G(alphaq) signaling and activating G(alpha12,13) signaling. CU201 induced apoptosis and complete growth inhibition in various lung cancer and other cancer cell lines. CU201 was 10-fold more potent than substance P derivatives and was stable in serum for >7 days. In this study, we evaluated the ability of CU201 to produce additive or synergistic growth inhibition in combination with various antitumor agents used in lung cancer therapy. We found that CU201 produced additive or synergistic growth inhibition when combined with doxorubicin, etoposide, cisplatin, vinorelbine, and paclitaxel for SCLC lines and with paclitaxel and ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, for non-SCLC cell lines. Pharmacokinetic parameters associated with the i.v. administration of CU201 were evaluated in normal mice, and the effects of CU201 on the growth of human lung cancer xenografts were evaluated in athymic nude mice. In CD2F1 mice given an i.v. bolus infusion of 5 mg/kg, the c(max) was 5773 ng/ml (5 microM), and the decay was biexponential. When fitted to a two-compartment model, the t(1/2alpha) was 14.4 min, and the t(1/2beta) was 44.3 h, indicating a long terminal half-life consistent with the prolonged in vitro effects. CU201 inhibited the growth of human lung cancers in athymic nude mice by the intratumoral, s.c., and i.p. routes at a dose of 5 mg/kg/day. This dose is >10-fold less than the dose of substance P derivatives used to inhibit SCLC xenografts in nude mice. We conclude that CU201 should undergo further preclinical toxicology studies in its development as a novel targeted therapy for the treatment of lung cancers with neuroendocrine features. These studies are in progress through the NCI RAID mechanism.
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PMID:Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines in vitro and in vivo and produces synergistic growth inhibition in combination with other antitumor agents. 1200 49

1. The role of substance P and its high affinity neurokinin-1 receptor in colitis has not been fully elucidated. We assessed the participation of neurokinin-1 receptor in colitis using the 2,4,6,-trinitrobenzensulphonic acid and dextran sulphate-induced animal models of colitis and genetically-engineered, neurokinin-1 receptor-deficient mice. 2. Clinical signs, macroscopic and histologic damage associated with 2,4,6,-trinitrobenzensulphonic acid (12 days) and dextran sulphate (5 days) colitis were more severe in neurokinin-1 deficient than in wild-type mice, while immunoreactivities for epidermal growth factor and its receptor were similar in the colon of both mice strains before and after colitis. 3. Substance P, dose-dependently induced intestinal fibroblast proliferation and enhanced epidermal growth factor-induced proliferation in intestinal fibroblasts isolated from wild-type, but not from neurokinin-1 receptor deficient mice. 4. Substance P-induced intestinal fibroblast proliferation required the presence of epidermal growth factor receptor with kinase activity. Furthermore, substance P induced epidermal growth factor tyrosine phosphorylation and activation in normal intestinal fibroblasts. 5. Our results indicate that in mice lacking the neurokinin - 1 receptor, substance P plays a protective role in prolonged experimental colitis.
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PMID:Protective effects of neurokinin-1 receptor during colitis in mice: role of the epidermal growth factor receptor. 1201 Jul 76

Substance P receptor (SPR), a G protein-coupled receptor (GPCR), is found in human glioblastomas, and has been implicated in their growth. Consistent with a role for SPR in cell growth, activation of SPR in U373 MG human glioblastoma cells leads to the phosphorylation of mitogen-activated protein kinases [extracellular signal-regulated kinase 1 and 2 (ERK1/2)] and stimulation of cell proliferation. The purpose of the present study was to elucidate the pathway through which these actions occur. Using either the epidermal growth factor receptor (EGFR) kinase inhibitor, AG 1478, or a small-interfering RNA (siRNA) directed against human EGFR, we found that transactivation of EGFR by SPR is only marginally involved in SP-dependent ERK1/2 phosphorylation. Src, however, is shown to be a major component of SPR signaling because the Src kinase inhibitor, PP2, and a kinase-dead Src mutant both inhibit SP-dependent ERK1/2 phosphorylation. We also report that SPR stimulates the phosphorylation of protein kinase Cdelta(PKCdelta), and that this stimulation is blocked by PP2. SP-dependent ERK1/2 phosphorylation is also blocked by rottlerin, a PKCdelta inhibitor, and the calcium scavenger, BAPTA/AM. Finally, rottlerin and PP2 were both found to inhibit the growth of several glioblastoma cell lines, underscoring the potential of these agents to block glioblastoma growth.
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PMID:Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta. 1601 65

The protein C pathway is an important regulator of the blood coagulation system. Protein C may also play a role in inflammatory and immunomodulatory processes. Whether protein C or activated protein C affects lymphocyte migration and possible mechanisms involved was tested. Lymphocyte migration was studied by micropore filter assays. Lymphocytes that were pretreated with protein C (Ceprotin) or activated protein C (Xigris) significantly reduced their migration toward IL-8, RANTES, MCP-1, and substance P, but not toward sphingosine-1-phosphate. The inhibitory effects of protein C or activated protein C were reversed by Abs against endothelial protein C receptor and epidermal growth factor receptor. Evidence for the synthesis of endothelial protein C receptor by lymphocytes is shown by demonstration of receptor mRNA expression and detection of endothelial protein C receptor immunoreactivity on the cells' surface. Data suggest that an endothelial protein C receptor is expressed by lymphocytes whose activation with protein C or activated protein C arrests directed migration. Exposure of lymphocytes to protein C or activated protein C stimulates phosphorylation of Tyr845 of epidermal growth factor receptor, which may be relevant for cytoprotective effects of the protein C pathway.
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PMID:Endothelial protein C receptor-dependent inhibition of migration of human lymphocytes by protein C involves epidermal growth factor receptor. 1639 89

Substance P (SP) acting through substance P receptor (SPR) increases the proliferation of glioblastoma cells. At the molecular level, stimulation of SPR in human U373 MG glioblastoma cells results in phosphorylation of mitogen-activated protein kinases ERK1/2. Examination of the underlying mechanism reveals that SPR mediates ERK1/2 phosphorylation in a calcium-dependent manner. Surprisingly, blockade of epidermal growth factor receptor (EGFR), which is transactivated by SPR, has a minimal effect on SPR-mediated ERK1/2 phosphorylation. However, SPR-mediated ERK1/2 phosphorylation is significantly reduced by the Src kinase inhibitor PP2. Interestingly, ERK1/2 in U373 MG cells is also activated by several other mitogenic G protein-coupled receptors (GPCRs) including alpha(1B)-adrenergic, M(3)-muscarinic, and H(1)-histaminergic in an Src-dependent manner. We conclude that c-Src is a mediator of SP-stimulated ERK1/2 phosphorylation in human U373 MG glioblastoma cells.
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PMID:Substance P receptor in U373 MG human astrocytoma cells activates mitogen-activated protein kinases ERK1/2 through Src. 1809 97

Previous studies have shown that neurokinin 1 receptor (NK1R) occurs naturally in human glioblastomas and its stimulation causes cell proliferation. In the present study we show that stimulation of NK1R in human U373 glioblastoma cells by substance P increases Akt phosphorylation by 2.5-fold, with an EC(50) of 57 nM. Blockade of NK1R lowers basal phosphorylation of Akt, indicating the presence of a constitutively active form of NK1R; similar results are seen in U251 MG and DBTRG-05 glioblastoma cells. Linkage of NK1R to Akt implicates NK1R in apoptosis of glioblastoma cells. Indeed, treatment of serum-starved U373 cells with substance P reduces apoptosis by 53 +/- 1% (p < 0.05), and treatment with NK1R antagonist L-733,060 increases apoptosis by 64 +/- 16% (p < 0.01). Further, the blockade of NK1R in human glioblastoma cells with L-733,060 causes cleavage of Caspase-3 and proteolysis of poly (ADP-ribose) polymerase. Experiments designed to elucidate the mechanism of NK1R-mediated Akt phosphorylation revealed total involvement of non-receptor tyrosine kinase Src and phosphatidyl-3-kinase, a partial involvement of epidermal growth factor receptor, and no involvement of mitogen-activated protein/extracellular signal-related kinase. Taken together, the results of the present study indicate a key role for NK1R in glioblastoma apoptosis.
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PMID:A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. 1951 79

Airway mucus hypersecretion is a significant clinical and pathological feature of chronic inflammatory airway diseases. Its clinical presentations include recurrent coughing and phlegm. Airway mucus is closely associated with the occurrence, development and prognosis of chronic inflammatory airway diseases and critically affects the lung function, quality of life, hospitalization rate and mortality of patients with chronic inflammatory airway diseases. Therefore, expectorant therapies targeting the potential mechanisms of mucus hypersecretion have been the focus of numerous studies. Conventional expectorants are mainly mucoactive medicines, including nausea-stimulating expectorants, mucolytics, mucokinetics, and proteases and nucleases. In addition, certain traditional Chinese herbal medicines and non-mucoactive agents, including muscarinic acetylcholine receptor antagonists, corticosteroids, leukotriene receptor antagonists and macrolide antibiotics, have also shown expectorant effects. Several novel medicines for expectorant therapy have emerged, including cholesterol-lowering statins, epidermal growth factor receptor tyrosine kinase inhibitors, phosphodiesterase-4 inhibitors, stanozolol, surfactants, flavonoids, tachykinin receptor antagonists, protease inhibitors, cytokine antagonists and purinergic agonists. With the increasing number of multidisciplinary studies, the effectiveness of expectorant therapy for the treatment of chronic inflammatory airway diseases has been confirmed. Therefore, the development of novel expectorants and the standardization of expectorant therapy are the direction and focus of future studies, thus benefiting patients who have a chronic inflammatory airway disease.
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PMID:Clinical application of expectorant therapy in chronic inflammatory airway diseases (Review). 2466 26


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