UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrin has been postulated to be a physiological growth factor, but compelling in vitro evidence of this has been difficult to obtain. In the present study we investigated whether small cell lung carcinoma cell lines could provide a useful model system to study the effects of gastrin on signal transduction and cell proliferation in vitro. We found that the addition of gastrin to small cell lung cancer cells loaded with the fluorescent Ca2+ indicator fura 2-tetraacetoxymethylester causes a rapid and transient increase in the intracellular concentration of Ca2+ ([Ca2+]i) followed by homologous desensitization. The [Ca2+]i response was especially prominent in the small cell lung carcinoma cell line H510. In this cell line, gastrin I, gastrin II, cholecystokinin residues 26-33 (CCK-8), and unsulfated CCK-8 increased [Ca2+]i in a concentration-dependent fashion with half-maximum effects at 7, 2.5, 3, and 5 nM, respectively. The Ca(2+)-mobilizing effects of gastrin and CCK-8 were prevented by proglumide, benzotript, and the specific gastrin/CCKB receptor antagonist L365260. Gastrin stimulated the clonal growth of H510 cells in semisolid (agarose-containing) medium, increasing both the number and the size of the colonies. Gastrin and CCK agonists were equally effective in promoting clonal growth. The broad-spectrum neuropeptide antagonists [D-Arg1,D-Phe5,D-Trp7,9,Leu11] substance P and [Arg6,D-Trp7,9,MePhe8] substance P (6-11) markedly inhibited gastrin-stimulated Ca2+ mobilization and clonal growth. These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract.
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PMID:Gastrin stimulates Ca2+ mobilization and clonal growth in small cell lung cancer cells. 132 22

The neurokinin-1 (NK-1, substance P) receptor belongs to the class of seven transmembrane domain (7-TM) receptors that interact with cellular effector systems via guanine nucleotide binding regulatory proteins (G-proteins). In this study, coupling mechanisms of functional NK-1 receptors endogenously expressed in a human astrocytoma cell line (U373MG) were analyzed. Stimulation with substance P (SP) resulted in 1) a rapid increase in inositol 1,4,5-trisphosphate (IP3) synthesis; 2) a rise in cytosolic free calcium concentration ([Ca2+]i); 3) induction of immediate early gene transcription as monitored by c-fos and c-jun expression; and 4) a significant increase in de novo DNA synthesis. Thus, the functional responses induced by stimulation of NK-1 receptors on U373MG strongly correlate with those observed after treatment of primary astrocytes with SP and make U373MG cells a useful in vitro model system for the analysis of NK-1 receptor function on astrocytes in vivo.
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PMID:Functional characterization of neurokinin-1 receptors on human U373MG astrocytoma cells. 132 53

Previously, gastrin-releasing peptide (GRP) receptors were identified on small-cell lung cancer (SCLC) cells and GRP functioned as a SCLC autocrine growth factor. Here the effects of neuromedin B (NMB) on SCLC cells were investigated. [125I-Tyr0]NMB bound with high affinity to three of seven SCLC cell lines examined. [125I-Tyr0]NMB bound to SCLC cell line NCI-H209 and NCI-H345 in a time-dependent and reversible manner. [125I-Tyr0]NMB bound with high affinity (Kd = 1 nM) to a single class of sites (Bmax = 800/cell). Specific [125I-Tyr0]NMB binding was inhibited with high affinity by NMB (IC50 = 1 nM) and moderate affinity by bombesin, GRP and [D-Arg1, D-Pro2, D-Trp7,9, Leu11]substance P ([APTTL]SP) but not GRP1-16 (IC50 = 50, 100, 1,000 and > 10,000 nM, respectively). In Fura 2 AM loaded NCI-H345 cells, NMB elevated cytosolic calcium in a concentration-dependent manner. NMB (10 nM) elevated the cytosolic calcium from 150 to 180 nM and calcium was released from intracellular pools. The increase in cytosolic calcium caused by 10 nM NMB was reversed by 1 microM [APTTL]SP but not 1 microM [D-Phe6]bombesin6-13methylester, a GRP receptor antagonist. Also, NMB stimulated the clonal growth of NCI-H209 and NCI-H345 in a concentration-dependent manner. The increase in the clonal growth caused by NMB was reversed by 1 microM [APTTL]SP. These data suggest that NMB receptors may regulate the proliferation of some SCLC cells.
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PMID:Neuromedin B binds with high affinity, elevates cytosolic calcium and stimulates the growth of small-cell lung cancer cell lines. 132 11

The calcium current of frog sympathetic neurons has relatively rapid activation kinetics (tau < 3 ms) in response to changes in voltage. Pharmacologically, the current is blocked approximately 90% of omega-conotoxin, but < 10% by dihydropyridine antagonists. This suggests that nearly all of the current is N type. However, inactivation is slow and incomplete even for depolarizations lasting > 1 s, consistent with recent evidence that N-type channels do not always inactivate rapidly. The calcium current is partially inhibited via receptors for acetylcholine, luteinizing hormone releasing hormone, substance P, ATP, and norepinephrine. These effects are mimicked by internal dialysis with GTP-gamma-S, suggesting involvement of a G protein. The transmitters affect the activation kinetics of the calcium current in a voltage-dependent manner, which can be modeled as a reversible shift of some channels to "reluctant" states in which strong depolarization is needed to produce channel opening. The effects of transmitters develop and recover with t1/2 approximately 1-2 s, so if a second messenger is involved in receptor-calcium channel coupling, it must act rapidly.
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PMID:Separation and modulation of calcium currents in bullfrog sympathetic neurons. 133 98

Administration of i.t. calcium has been shown to produce effects which are opposite to those observed when calcium is injected into the brain. The purpose of this study was to elucidate the mechanism of the antinociceptive action of calcium (i.t.). Injection of calcium (i.t.) produced antinociceptive effects in the tail-flick and p-phenylquinone (PPQ) stretching tests. The ED50 value for calcium (i.t.) in the PPQ test was 4.8 (4.2-5.5) nmol per mouse vs. 344 (251-469) nmol per mouse for calcium (i.t.) in the tail-flick test. The antinociceptive effects of calcium (i.t.) were attenuated significantly in the tail-flick test by pretreatment with naloxone (i.t.) (AD50 value = 200 pmol/mouse) and ICI-174,864 (i.t.) (AD50 value = 20 nmol/mouse), but not by the kappa receptor-selective antagonist nor-BNI. The antinociceptive effects of calcium (i.t.) were attenuated significantly in the PPQ test by pretreatment with naloxone (i.t.) (AD50 value = 50 pmol/mouse) and norbinaltorphimine (i.t.) (AD50 value = 110 pmol/mouse), but not by the delta receptor-selective antagonists naltrindole and ICI-174, 864. Administration of calcium (i.t.) significantly enhanced the antinociceptive effects of mu [D-Ala2,N-Me-Phe4,Gly-ol]enkephalin, delta [D-Pen2,D-Pen5]enkephalin and kappa (U50,488H) opioid receptor-selective peptides. The injection of the dibutyryl derivative of cyclic AMP (i.t.), as well as forskolin (i.t.), blocked the antinociceptive effects of calcium (i.t.) (AD50 values = 39 nmol and 1.7 nmol/mouse, respectively). Injection of apamin (AD50 value = 2.9 pmol/mouse) and charybodotoxin (58 fmol/mouse), blockers of calcium-gated potassium channels, significantly blocked calcium (i.t.). The antinociceptive effects of calcium (i.t.) were also blocked by verapamil (30 and 60 nmol/mouse), theophylline (275 nmol/mouse) and substance P (7.4 nmol/mouse, i.t.). Thus, the data indicate that the mechanism underlying the antinociceptive effect of calcium (i.t.) involves mediation, at least in part, by opioid peptides, alterations in intraneuronal cyclic AMP and/or neuronal hyperpolarization, and decreased release of substance P. The administration of calcium (i.t.) may also enhance the release of adenosine as a significant factor in the antinociceptive effects of the calcium.
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PMID:A proposed mechanism of action for the antinociceptive effect of intrathecally administered calcium in the mouse. 134 58

1. Whole-cell calcium currents of bullfrog sympathetic neurones were partially inhibited by noradrenaline (NA), chicken-II-luteinizing hormone-releasing hormone (LHRH), muscarine, ATP, substance P, or intracellular dialysis with guanosine 5'-O-(3-thiotriphosphate)(GTP-gamma-S) or aluminium fluoride. These agents had similar effects on the activation kinetics of calcium current. 2. The amplitude of the LHRH effect varied from cell to cell. This did not correlate with cell size or the time of whole-cell dialysis. 3. The response to LHRH desensitized rapidly. Desensitization to LHRH did not affect inhibition by NA, ATP or substance P. 4. The effects of LHRH and NA were partially additive. 5. Cells dialysed with GTP-gamma-S still responded to NA or LHRH. However, NA or LHRH inhibited a smaller fraction of the calcium current than usual, and second applications of the same transmitter to GTP-gamma-S-dialysed cells were ineffective. 6. In GTP-gamma-S-dialysed cells, application of LHRH occluded the response to NA, but LHRH was still effective after application of NA. 7. The effect of GTP-gamma-S decreased during prolonged dialysis. 8. The effect of NA was selectively reduced by intracellular dialysis with the A-protomer of pertussis toxin (PTX), or extracellular pretreatment with high concentrations of whole PTX at room temperature. These treatments had little or no effect on the action of LHRH or ATP. 9. It is concluded that multiple G proteins can produce identical changes in calcium channel gating. The adrenergic receptor preferentially couples to a PTX-sensitive G protein.
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PMID:Calcium current modulation in frog sympathetic neurones: multiple neurotransmitters and G proteins. 135 63

Besides their neurotransmitter and/or neuromodulatory roles, many neuroactive substances synthesized and released during brain development can also directly influence neuronal differentiation. Transitory expression of neurotransmitters, their metabolic enzymes and their receptors is only one aspect of this trophic role. The most considerable progress in neurotrophic factor research has been made with the use of primary cultures of neuronal cells, and numerous studies have focused on the effects of neurotransmitters on the differentiation of cells at various stages of development. Thus, several neuropeptides like VIP, substance P, enkephalins, somatostatin, and monoamines, can modulate neuronal differentiation, but only during a limited period of fetal life. Among the monoamines, it was shown that, depending on the target, 5-HT stimulates the development of the neuropile, the myelinization of axons, the differentiation of the synaptic contacts, induces markers of monoaminergic neuron differentiation, inhibits the development of the growth cone, decreases the branching of neurites, and influences the survival, cell body size, and neurite outgrowth in several neuronal cultures. 5-HT can also indirectly influence the differentiation of serotonergic neurons by the intermediate of astrocytes, and it was shown in our laboratory that 5-HT1A agonists can stimulate the cholinergic parameters of primary cultures of rat fetal septal neurons. At the molecular level, the events triggered by neurotransmitters that underlie their neurotrophic action probably involve the transmembrane influx of calcium. To date, calcium regulation of cellular processes is one of the most rapidly expanding areas of research in developmental neurobiology.
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PMID:Trophic effects of neurotransmitters during brain maturation. 135 26

Central and peripheral alpha 2-adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically-stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) of the guinea-pig ileum was found to be resistant to the action of the alpha 2-adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform-induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the alpha 2-adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, Ca(2+)-free, K(+)-depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+ entry blocker nifedipine. Both chlordimeform- and nifedipine-induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform-induced depression of motor activity in the guinea-pig ileum is, at least in part, related to inhibition of transmembrane Ca2+ fluxes responsible for smooth muscle contraction.
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PMID:Calcium entry blockade as a mechanism for chlordimeform-induced inhibition of motor activity in the isolated guinea-pig ileum. 136 68

When primary cultured bovine adrenocortical cells were treated with substance P (SP) at concentrations higher than 10 pM, cortisol output increased in a dose-dependent fashion. Although other neurokinins, such as neurokinin A (NKA) and neurokinin B (NKB), were also effective in secreting cortisol, SP was the most potent among the tested neurokinins, the potency order being SP greater than NKA much greater than NKB. This suggests that the NK-1 type receptor on adrenocortical cells may be the site of action of SP on cortisol secretion. The maximal response in SP-induced cortisol secretion was comparable to that elicited by adrenocorticotropic hormone (ACTH). SP-induced cortisol secretion was dependent upon extracellular Ca2+ concentrations, and 45Ca2+ uptake into adrenocortical cells treated with SP was long-lasting. While, in the case of ACTH, 45Ca2+ uptake proceeded transiently, the increase in intracellular cAMP content was much greater compared with that of SP. Although KT-5720, an inhibitor of protein kinase A, inhibited potently ACTH-induced cortisol secretion, SP-induced secretin was not affected by this inhibitor at all. On the other hand, calmodulin inhibitors, such as calmidazolium, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, were not more effective in inhibiting SP-induced cortisol secretion than secretion induced by ACTH. The present study indicates that SP may be one of the physiological stimulants of cortisol secretion and that an increase in intracellular Ca2+ concentration and the subsequent activation of calmodulin may precede SP-induced cortisol secretion.
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PMID:Cortisol secretion induced by substance P from bovine adrenocortical cells and its inhibition by calmodulin inhibitors. 137 83

The characteristics of Ca2+ entry activated by surface receptor agonists and membrane depolarization were studied in the rat pancreatoma cell line, AR4-2J. Ca2+ mobilization activated by substance P, bombesin, or muscarinic receptor stimulation was found to involve both Ca2+ release and entry. In addition, depolarization of the surface membrane of AR4-2J cells with elevated concentrations of K+ activated Ca2+ entry. Ca2+ entry induced by membrane depolarization was inhibited by the L-channel antagonist, nimodipine, while that due to surface receptor agonists was not inhibited by this agent. The microsomal Ca(2+)-ATPase inhibitor, thapsigargin, caused both depletion of the agonist-sensitive intracellular Ca2+ pool and sustained Ca2+ influx indistinguishable from that produced by bombesin or methacholine. These results confirm that, unlike the pancreatic acinar cells from which they are presumably derived, AR4-2J cells express voltage-sensitive, dihydropyridine-inhibitable Ca2+ channels. However, in contrast to previous reports with this cell line, in the AR4-2J cells in use in our laboratory, and under our experimental conditions, surface receptor agonists (including substance P) do not cause Ca2+ influx through voltage-sensitive Ca2+ channels. Instead, we conclude that agonist-activated Ca2+ mobilization is initiated by (1,4,5)IP3-mediated intracellular Ca2+ release and that Ca2+ influx is regulated primarily, if not exclusively, by the state of depletion of the (1,4,5)IP3-sensitive intracellular Ca2+ pool.
Cell Calcium 1992 Jan
PMID:Mechanisms of activated Ca2+ entry in the rat pancreatoma cell line, AR4-2J. 137 21

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