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

Neurokinins are a family of neuropeptides with widespread distribution mediating a broad spectrum of physiological actions through three distinct receptor subtypes: NK-1, NK-2, and NK-3. We investigated some of the second messenger and cellular processes under control by the recombinant bovine NK-2 receptor stably expressed in Chinese hamster ovary cells. In this system the NK-2 receptor displays its expected pharmacological characteristics, and the physiological agonist neurokinin A stimulates several cellular responses. These include 1) transient inositol 1,4,5-trisphosphate (IP3) formation and Ca2+ mobilization, 2) increased out put of arachidonic acid and prostaglandin E2 (PGE2), 3) enhanced cyclic AMP (cAMP) generation, 4) increased de novo DNA synthesis, and 5) an induction of the "immediate early" genes c-fos and c-jun. Although NK-2 receptor-mediated IP3 formation involves activation of a pertussis toxin-insensitive G-protein, increased cAMP production is largely a secondary response and can be at least partially attributed to autocrine stimulation by endogenously generated eicosanoids, particularly PGE2. This is the first demonstration that a single recombinant neurokinin receptor subtype can regulate, either directly or indirectly, multiple signal transduction pathways and suggests several potential important mediators of neurokinin actions under physiological conditions.
 ...
PMID:Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways. 166 1

The tachykinin family of neuropeptides, including substance P and neurokinins A and B, induce a transient increase in intracellular free calcium concentration in human small cell lung carcinoma (SCLC) cells, as measured with a calcium indicator fura-2. The effects are dose dependent and even greater than that of bombesin at equimolar concentrations in these cells. The tachykinins, like bombesin, induce calcium mobilization mainly from intracellular store(s). None of the peptides, however, shows a stimulatory effect on DNA synthesis. In addition, exogenously applied bombesin does not stimulate DNA synthesis at any concentration tested. We also examined the effects of a recently reported bombesin antagonist [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P in SCLC cells, and compared them to those in Swiss 3T3 fibroblasts in which the mitogenic effect of bombesin is well characterized. The antagonist at 10(-5) M completely abolishes the Ca2+-mobilizing effect of 10(-7) M bombesin in SCLC cells, and that of 10(-9) M but not 10(-7) M bombesin in Swiss 3T3 cells. The antagonist at this concentration effectively inhibits the mitogenic action of bombesin (10(-9) M) in Swiss 3T3 cells; however, much higher doses (approximately 10(-4) M) are needed to inhibit DNA synthesis in SCLC cells. Moreover, the antagonist inhibits DNA synthesis in bombesin/gastrin-releasing peptide-nonproducing cells with a similar dose dependency as in producing cells. These results indicate that bombesin/gastrin-releasing peptide and other calcium mobilizing peptides do not always act as a growth factor in SCLC cells, and that the bombesin antagonist could inhibit growth of SCLC cells through a mechanism other than bombesin antagonism.
 ...
PMID:Stimulation of calcium mobilization but not proliferation by bombesin and tachykinin neuropeptides in human small cell lung cancer cells. 168 10

In the search for novel antiproliferative agents for small cell lung cancer (SCLC), we found the neuropeptide antagonist [Arg6, D-Trp7,9,MePhe8]substance P(6-11) to be effective in vitro. In murine Swiss 3T3 cells [Arg6,D-Trp7,9,MePhe8]substance P(6-11) was identified as a potent inhibitor of vasopressin-stimulated DNA synthesis which also blocks [3H]vasopressin binding to specific cell-surface receptors. It was a less potent antagonist of gastrin-releasing peptide and bradykinin in these cells but did not block the effects of other mitogens. In SCLC cell lines, [Arg6,D-Trp7,9,MePhe8]substance P(6-11) inhibited colony-formation in soft agarose and growth in liquid culture in a dose-dependent manner. It also blocked receptor-mediated Ca2+ mobilization induced by vasopressin, bradykinin, cholecystokinin, galanin, gastrin-releasing peptide, and neurotensin. We suggest that broad-spectrum neuropeptide antagonists can block multiple autocrine and paracrine growth loops in SCLC and could be useful therapeutic agents.
 ...
PMID:A neuropeptide antagonist that inhibits the growth of small cell lung cancer in vitro. 169 79

Endothelin (ET1) and vasoactive intestinal contractor (VIC) stimulate quiescent Swiss 3T3 cells to resume DNA synthesis acting synergistically with epidermal growth factors (EGF) and other mitogens. The peptide [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P has been identified as a broad spectrum neuropeptide antagonist which blocks the binding and biological effects of the Ca2(+)-mobilizing neuropeptides bombesin, vasopressin, and bradykinin. In the present study we show that [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P also acts as an ET1/VIC antagonist as judged by the following criteria: a) inhibition of specific 125I-labelled ET1 binding to a ET1/VIC receptor in a competitive and dose-dependent manner; b) blocking of the rapid increase in the cytosolic Ca2+ concentration promoted by ET1 or VIC; and c) inhibition of DNA synthesis stimulated by VIC in the presence of EGF. The inhibitory effects of [D-Arg1,D-Phe5,D-Trp7,9,Leu 11] substance P on Ca2+ mobilization and DNA synthesis were reversed by increasing the concentration of VIC. This is the first time that a peptide structurally unrelated to ET1 or VIC is shown to block the binding and mitogenic effects of peptides of the endothelin family.
 ...
PMID:[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, a neuropeptide antagonist, blocks binding, Ca2(+)-mobilizing, and mitogenic effects of endothelin and vasoactive intestinal contractor in mouse 3T3 cells. 169 96

1. The long-term influence of substance P (SP) and vasoactive intestinal peptide (VIP) on rat salivary gland weight was investigated after parasympathetic denervation or on feeding soft food. 2. The parotid gland lost about one-third of its weight within 4-5 days following parasympathetic post-ganglionic denervation or change in dietary regimen, from pellets to liquid diet, thought to reduce nerve reflex activity. 3. Daily i.v. infusions with SP or VIP diminished or largely prevented the fall in parotid gland weight, whereas infusions with pentagastrin, bethanechol and saline had no effect. The infusions were preceded by administration of alpha- and beta-adrenoceptor antagonists; these antagonists were also given to the control animals. 4. The effect of SP and VIP on the parotid gland weight appeared to be related to cell size rather than to cell number, as judged by measurements of RNA and DNA. 5. Observations on the two other major salivary glands underlined the fact that different gland types in the same animal behave differently. Parasympathetic preganglionic denervation (decentralization) lowered the weights of the sublingual and submandibular glands, whereas liquid diet only reduced the weight of the sublingual gland. SP and VIP did not affect the weights of the submandibular glands, but VIP prevented the slight fall in sublingual gland weight induced by liquid diet. 6. The present results suggest a trophic role in rats for SP and VIP on parotid glands and for VIP on sublingual glands. Such an influence may be exerted naturally as a result of their release from nerves containing these peptides around acini.
 ...
PMID:Effects of repeated infusions of substance P and vasoactive intestinal peptide on the weights of salivary glands subjected to atrophying influences in rats. 170 5

We present a strategy to study functional and/or developmental processes occurring in the nervous system, as well as in other systems, of mice. This strategy is based on the local expression of specific monoclonal antibodies (mAbs) by cells of the nervous system. As an application of this strategy, we report the cloning of the anti-substance P rat mAb NC1/34HL. Functional substance P-binding antibodies were reconstituted from the cloned variable domains by using vectors for expression in myeloma cells. With these and other vectors a general system for the cloning and expression of mAbs under a series of promoters (of the rat VGF8a gene, the neurofilament light-chain gene, and the methallothionein gene) has been created. The activity of these plasmids was confirmed by expressing the recombinant NC1/34HL mAb in GH3 pituitary cells, PC12 pheochromocytoma cells, and COS cells. DNA from the described constructs can be used to target the expression of the NC1/34HL mAb to the central nervous system of transgenic mice. This procedure will allow us to perturb substance P activity in a controlled way in order to dissect its multiple roles.
 ...
PMID:Neuroantibodies: molecular cloning of a monoclonal antibody against substance P for expression in the central nervous system. 171 2

The use of a somatostatin analogue (SMS 201-995) has greatly facilitated the treatment of patients with the midgut carcinoid syndrome. Clinical studies have shown that SMS reduces the peripheral levels of tumour-produced serotonin (5-HT) and tachykinins, e.g. neuropeptide K (NPK), basally and after pentagastrin provocation. Some studies have indicated an inhibitory effect of SMS on tumour cell growth as well. In the present study we have investigated the effects of SMS on four different human midgut carcinoid tumours maintained in long term culture. Media levels of 5-HT and NPK-LI in tumour cell cultures decreased rapidly during incubation with SMS (10(-8)-10(-10) M) in all four tumours studied without evidence for tachyphylaxis (up to 6 weeks observation period). SMS treatment (10(-8) M) during 4 days reduced the media concentrations of 5-HT by 56%, while the intracellular contents of 5-HT were decreased by 27% indicating dual inhibitory effects on synthesis and secretion of 5-HT from tumour cells. The DNA contents of cultures were not affected by SMS (10(-8) M or 10(-10) M) treatment for 4 or 14 days. When tumour cell cultures were challenged with isoprenaline (IP) (10(-6) M) no reduction of the IP induced release of 5-HT could be detected after pretreatment of tumour cell cultures with SMS (10(-8) M) for 1 h, 4 h or 4 days. These studies provide evidence for a direct action of the somatostatin analogue on midgut carcinoid tumour cells, reducing both synthesis and secretion of hormones from tumour cells. This effect appears not to be related to inhibition of tumour cell growth. The inhibition of 5-HT secretion from tumour cells by SMS seems to operate via a second messenger system different from the one mediating the beta-adrenoceptor stimulated release of 5-HT.
 ...
PMID:The effect of a somatostatin analogue on the release of hormones from human midgut carcinoid tumour cells. 171 51

The production of substance P and the mRNA encoding its precursor (preprotachykinin, PPT) is regulated by nerve growth factor (NGF) in dorsal root ganglion (drg) neurons. To explore the mechanism by which NGF regulates the production of PPT mRNA, we have transfected PC12 cells and F11 cells with plasmids containing the bovine PPT promoter linked to the reporter gene chloramphenicol acetyltransferase (CAT). We have identified (i) functional elements within the PPT promoter which are necessary for expression in the absence of NGF and (ii) two separate regions, each of approximately 250 bp, which confer NGF responsiveness. Both regions contained a sequence element, similar to a known transcription factor binding site, which is present in several other NGF-regulated genes.
DNA Cell Biol 1991 Dec
PMID:Identification of nerve growth factor-responsive sequences within the 5' region of the bovine preprotachykinin gene. 174 55

The primary structure of the human substance K receptor was established from the sequences of complementary DNA clones isolated from a human jejunal complementary DNA library. It consists of 398 amino acids, including seven putative transmembrane regions. The gene for the human substance K receptor was localized to chromosome region 10p13-10q23, a region with frequent chromosomal abnormalities. The human substance K receptor was expressed in transfected NIH-3T3 cells lacking endogenous substance K receptors, and Scatchard analysis of 125I-labeled substance K binding indicates approximately 100,000 receptors/cell with a single dissociation constant of 12 nM. Covalent cross-linking experiments utilizing 125I-substance K and three different chemical cross-linking reagents (disuccinimidyl suberate, disuccinimidyl tartrate, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl) demonstrate an apparent molecular weight of 45,000, consistent with little or no N-linked glycosylation. The binding of substance K to its receptor on transfected cells led to a rapid increase in the production of total inositol phosphates and the release of Ca2+ from internal stores. Growth of the cells transfected with the human substance K receptor is stimulated by the addition of substance K to the medium to a level similar to 10% serum. Therefore, the human substance K receptor can function as a growth factor receptor when expressed in mouse 3T3 cells.
 ...
PMID:Cloning and expression of the human substance K receptor and analysis of its role in mitogenesis. 184 73

We investigated effects of various agents on proliferation, intracellular pH (pHi), and intracellular calcium [( Ca2+]i) of rat mesangial cells (MCs) in early passages (2-5). Serum-starved MCs incubated in HCO3- were exposed to one of the following: fetal calf serum (FCS), serotonin, angiotensin II (ANG II), arginine vasopressin (AVP), bombesin (Bom), bradykinin (BK), epidermal growth factor (EGF), epinephrine (Epi), interleukin 1 (IL-1), norepinephrine (NE), neuropeptide Y, oxytocin, substance P (SP), platelet-derived growth factor, or 12-O-tetradecanoylphorbol-13-acetate (TPA). We assessed DNA synthesis from [3H]thymidine uptake during exposure to test agent. All agents except ANG II, NE, Bom, and SP were mitogenic. When MCs were incubated in a HCO3(-) -free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, maximal mitogenic responses to FCS, AVP, and EGF were 41, 44, and 55% (P less than 0.01) lower, respectively, than those in presence of HCO3-. In absence of HCO3-, agents other than BK and IL-1 produced a biphasic pHi response characterized by a transient acidification followed by a prolonged alkalinization that was both Na(+)-dependent and amiloride-sensitive. In presence of HCO3-, agents produced only a small and gradual acidification, except for IL-1 and Epi. Addition of all agonists except IL-1, EGF, and TPA produced significant transient increases in [Ca2+]i, the magnitudes of which were similar in HCO3- and non-HCO3- buffers. These results demonstrate that, in presence of HCO3-, agents (i.e., NE and ANG II) can produce typical [Ca2+]i transients and still not cause MC proliferation. Conversely, an agent may cause proliferation without eliciting a short-term change in either [Ca2+]i or pHi (i.e., IL-1), a change in [Ca2+]i but not pHi (i.e., Epi), or a change in pHi but not [Ca2+]i (i.e., TPA). Thus, at least for MCs, proliferation in HCO3- can be dissociated from early agonist-induced changes in pHi and [Ca2+]i.
 ...
PMID:Effects of mitogens and other agents on rat mesangial cell proliferation, pH, and Ca2+. 211 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>