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)

Receptors for regulatory peptides (hormones or neurotransmitters) play a pivotal role in the ability of cells to taste the rich neuroendocrine environment of the gut. Recognition of low concentration of peptides with a high specificity and translation of the peptide-receptor interaction into a biological response through different signalling pathways (adenylyl cyclase-cAMP or phospholipase C-phosphatidylinositol) are crucial properties of receptors. While many new receptors have been identified and thereafter characterized functionally during the 1980s, molecular biology now emerges as the privileged way for the structural characterization and discovery of receptors. Different strategies of receptor cloning have been developed which may or may not require prior receptor purification. Among cloning strategies that do not require receptor purification, homology screening of cDNA libraries, expression of receptor cDNA or mRNA in Xenopus laevis oocytes or in COS cells, and the polymerase chain reaction method achieved great success, e.g. cloning of receptors for cholecystokinin, gastrin, glucagon-like peptide 1, gastrin-releasing peptide/bombesin, neuromedin K, neuropeptide Y, neurotensin, opioids, secretin, somatostatin, substance K, substance P and vasoactive intestinal peptide. All these receptors belong to the superfamily of G-protein-coupled receptors which consist of a single polypeptide chain (350-450 amino acids) with seven transmembrane segments, an N-terminal extracellular domain and a C-terminal cytoplasmic domain. In this chapter, we have detailed the properties of three receptors which play an important role in digestive tract physiology and illustrate various signal transduction pathways: pancreatic beta-cell galanin receptors which mediate inhibition of insulin release and intestinal epithelial receptors for vasoactive intestinal peptide and peptide YY, which mediate the stimulation and inhibition of water and electrolyte secretion, respectively.
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PMID:Receptors for gut regulatory peptides. 751 Sep 49

The effects of substance P (SP) upon basal and forskolin-stimulated cAMP production have been investigated in UC11MG cells. The cells expressed 40,000 NK1 receptors/cell, the stimulation of which led to enhanced phosphoinositide breakdown. Forskolin (10 and 100 mcM) stimulated cAMP production, whereas SP (3 and 300 nM) produced no significant increase in cAMP production. However, SP enhanced the response to forskolin, with an EC50 value of about 10 nM. The response to forskolin was also enhanced by physalaemin and eledoisin, and was sensitive to inhibition by (+/-)CP96345. It is concluded that in the UC11MG cell line, SP not only stimulates phosphoinositide breakdown but also enhances the cAMP response to forskolin, possibly via stimulation of NK1 receptors.
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PMID:Substance P enhances forskolin-stimulated cyclic AMP production in human UC11MG astrocytoma cells. 751 37

Neuropeptides were examined for their effects on the survival of cultured rat superior cervical ganglion cells after acute deprivation of nerve growth factor (NGF). Vasoactive intestinal peptide (VIP, 3 microM) delayed the neuronal death about 6 h alone. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.2 mM) greatly potentiated its effect, reducing EC50 from 2.5 microM to 8 nM. The neuronal death was completely suppressed under this condition. On the other hand, substance P (1-100 microM) or enkephalin (1-100 microM) alone did not modify the death, whereas the latter (100 microM) enhanced the survival-promoting effect of membrane depolarization with elevated K+. These results suggest strongly that neuropeptides regulate the NGF-independent survival of sympathetic neurons through a cAMP-dependent mechanism.
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PMID:Vasoactive intestinal peptide suppresses neuronal cell death induced by nerve growth factor deprivation in rat sympathetic ganglion cells in vitro. 751 83

Because endothelin-1 (ET-1) may be a neuromodulator in sensory systems, we examined whether this peptide could alter release of substance P (SP) and calcitonin gene-related peptide (CGRP) from isolated sensory neurons. Although ET-1 had minimal actions on spontaneous neuropeptide release, pretreating cultures with 500 nM resulted in a 50% augmentation of SP and CGRP release evoked by 50 nM capsaicin. Moreover, 2000 nM ET-1 enhanced capsaicin-evoked release of CGRP two fold. In an analogous manner, ET-1 alone did not alter intracellular cGMP content, but enhanced the increase in cGMP caused by 50 nM capsaicin. Intracellular cAMP was not altered by capsaicin and/or ET-1. These data suggest that ET-1 may play a role in modulation of peptide release from primary afferent neurons.
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PMID:Endothelin-1 enhances capsaicin-induced peptide release and cGMP accumulation in cultures of rat sensory neurons. 751 37

In this study we report that substance P stimulated [3H]glycogen breakdown and elevation of intracellular Ca2+ concentration in the human astrocytoma cell line UC-11MG. Both effects were dose dependent, and completely blocked by CP-96,345 suggesting the involvement of an NK1 receptor. Our previous studies indicated that norepinephrine and histamine stimulate glycogenolysis via cAMP and Ca2+ respectively. Combined stimulation with substance P and norepinephrine or histamine resulted in additive effects suggesting that there is no interaction between these neurotransmitters in regulating glycogenolysis in these cells. These results confirm that UC-11MG cells are a useful model system to investigate the functional role of neurotransmitter receptors in astroglial cells.
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PMID:Substance P receptors on human astrocytoma cells are linked to glycogen breakdown. 751 38

The mammalian suprachiasmatic nucleus (SCN) has been identified as a circadian pacemaker. N-methyl-D-aspartate (NMDA), non-NMDA and substance P receptors have been suggested to be involved in handling of photic information in the SCN. In the Aplysia eyes, in which the circadian clocks are involved, serotonin- or cAMP-induced phase changes of the circadian rhythm were reported to be blocked by protein-synthesis inhibitors. Therefore, we investigated whether protein-synthesis inhibitor can block the non- NMDA receptor agonist (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA)- or substance P (SP)-induced phase changes of SCN activity rhythm. Although application of 10 microM cycloheximide alone during the early part of the subjective night did not cause phase change, it blocked both 10 microM AMPA- and 1 microM SP-induced phase delay. The present result suggests that protein synthesis may be required in the manifestation of AMPA- and SP-induced phase change of circadian clock.
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PMID:Protein-synthesis inhibitor blocks (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-or substance P-induced phase shift of the circadian rhythm of neuronal activity in the rat suprachiasmatic nucleus in vitro. 751 59

The human c-kit receptor ligand, rhSCF, is the only cytokine known to be active on human mast cells, but its intracellular signal transduction pathway is still unknown. We compared the effect of rhSCF on intracellular Ca2+ levels in purified (> 70% pure) adult skin mast cells with two other immunologic stimuli, namely, anti-IgE and substance P. Both rhSCF (1 microgram/mL) and anti-IgE (3 micrograms/mL) induced a rapid (< 20 sec) and sustained (T1/2 for decay > 10 min) increase in free cytosolic Ca2+ concentration. In contrast, substance P (5 microM) elicited a very rapid (< 1 sec) and transient (T1/2 for decay congruent to 5 sec) rise in intracellular Ca2+ levels. Intracellular cAMP levels were then increased by pharmacologic means to examine the role of the cyclic nucleotide in controlling the Ca2+ response in skin mast cells. A combination of the general phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) (200 microM) and the adenylate cyclase activator, forskolin (30 microM) was effective in inhibiting the Ca2+ response induced by rhSCF or anti-IgE (82 and 68% inhibition, respectively), while IBMX and forskolin alone were much less effective. The phosphodiesterase isozyme IV inhibitor, rolipram (10 microM), variably affected the increase in Ca2+ levels induced by anti-IgE, but it exerted a significant inhibitory activity on anti-IgE- or rhSCF-induced response in the presence of forskolin (30 micrograms/mL) (33 and 67%, respectively). Two different protein kinase C (PKC) activators TPA (200 nM) and bryostatin 1 (200 nM) similarly inhibited rhSCF- (22 and 32%, respectively) and anti-IgE-induced (24 and 32%) Ca2+ response. Finally, the kinase inhibitor genistein (30 micrograms/mL) was a somewhat more effective inhibitor of the rise in intracellular Ca2+ induced by rhSCF (100%) than that activated by anti-IgE (54%) (P < 0.05). These data indicate that rhSCF and anti-IgE may act on human mast cells through a common pathway to increase free cytosolic Ca2+ levels and this effect is similarly modulated by various drugs.
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PMID:Studies of the intracellular Ca2+ levels in human adult skin mast cells activated by the ligand for the human c-kit receptor and anti-IgE. 751 34

The neurokinin-1 tachykinin receptor is a member of the G protein-coupled receptor superfamily. An unusual feature of the neurokinin-1 receptor is the presence of glutamic acid (residue 78) in the second putative transmembrane domain, at the location of a highly conserved aspartate residue in the G protein-coupled receptor superfamily. The rat neurokinin-1 receptor cDNA was mutated to lysine, aspartate, and glutamine at this site and functionally expressed in Chinese hamster ovary cells, and clonal cell lines were isolated and characterized. Radioligand binding demonstrated that the Asp78 and Lys78 receptors have substance P binding affinities indistinguishable from those of the wild-type receptor and are expressed at roughly the same number of receptors per cell. The Gln78 receptor variant, on the other hand, exhibited no detectable agonist binding. Although wild-type and Asp78 receptors have essentially the same ability to stimulate inositol phospholipid turnover, cAMP production, and arachidonic acid release, the Lys78 variant is markedly attenuated in its ability to activate any of these pathways. These data indicate that residue 78 plays a role in the coupling of the rat neurokinin-1 receptor to cellular effectors. In addition, both Asp78 and Lys78 receptors show a greater percentage of high affinity binding that is resistant to guanosine-5'-O-(3-thio)triphosphate than does the wild-type receptor, indicating a potential difference in G protein coupling between wild-type and mutated receptors.
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PMID:Residue 78 in the second transmembrane domain of the neurokinin-1 receptor is important in coupling high affinity agonist binding to multiple second messenger responses. 753 94

We have reported previously that the rat insulinoma cell lines, RINm5F and RINr1046-38, express the preprotachykinin(PPT)-A gene, which encodes the tachykinin peptides, substance P and neurokinin A. Because endocrine cells of the adult rat pancreas do not appear to express PPT-A, we investigated whether the gene is expressed by rat pancreatic endocrine cells during development. We used immunohistochemistry, employing different substance P and neurokinin A antibodies, to show that many endocrine cells of the fetal and neonatal rat pancreas synthesise these products of PPT-A gene expression. Colabeling experiments revealed that a significant number of both insulin-containing and non-insulin-containing cells express tachykinins. After postnatal day 20, the number of tachykinin-immunoreactive pancreatic islet cells declines and, as already reported, none were detected in the adult rat pancreas. The transient expression of PPT-A by the developing endocrine pancreas is a novel finding. Substance P and neurokinin A are known to have trophic actions and may serve as growth factors during pancreatic islet development. PPT-A gene expression by RINm5F and RINr1046-38 cells is further evidence that these cells resemble developing pancreatic endocrine cells. They are potentially valuable as unique models for studying the regulation of tachykinin biosynthesis. We provide evidence in this study, using quantitative PPT-A messenger RNA analysis, that PPT-A expression in RINm5F cells may be up-regulated by activation of protein kinase C, down-regulated by activation of glucocorticoid receptors, and is not significantly affected by changes in intracellular cAMP levels.
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PMID:Preprotachykinin-A gene expression occurs transiently in the developing rat endocrine pancreas and can be regulated in RINm5F cells. 753 64

Releasability of mast cells and basophils to an IgE-dependent stimulus is regulated by extra- and intracellular factors which are only partly understood. As gangliosides are known to modulate receptor-dependent processes in various cell types, we have evaluated the effect of these molecules on mast cell mediator release. Human skin mast cells and the human mast cell line HMC1 were pretreated with the gangliosides GM2, GM3 and GD1a as well as with asialo-GM3, heparin and buffer alone (controls). After washing, the cells were stimulated with anti-IgE, calcium ionophore A 23187, N-FMLP or substance P. All gangliosides but not asialo-GM3 and heparin augmented anti-IgE-induced mediator release in a dose-dependent fashion, whereas the release to A 23187, N-FMLP and substance P remained unaffected. Only sequential but not simultaneous addition of ganglioside and anti-IgE showed an enhancement in mediator release compared to controls. Mediator release in both ganglioside-pretreated cells and controls was calcium-dependent and could be inhibited by pretreatment of cells with staurosporine or dibutyryl cAMP, indicating an unchanged signal transduction. Gangliosides appear to specifically optimize IgE-receptor-ligand interaction and alterations in cellular gangliosides could thus induce enhanced releasability as observed in atopics.
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PMID:Gangliosides enhance IgE receptor-dependent histamine and LTC4 release from human mast cells. 757 75


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