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)

Somatostatin, substance P, and vasoactive intestinal polypeptide were incubated in an adenylate cyclase assay with a particulate fraction of caudate-putamen tissue of the rat in order to examine the effect of the neuropeptides on G-protein coupled adenylate cyclase in vitro. Somatostatin induced an enhancement of cyclic AMP formation in presence of guanine nucleotides and cholera toxin but inhibited pertussis toxin and forskolin enzyme stimulation. Pertussis toxin and cholera toxin also depressed forskolin-induced stimulation as described previously. Somatostatin was able to antagonize these inhibitory effects of both toxins. On the contrary, substance P reduced GTP and cholera toxin stimulated striatal adenylate cyclase, without affecting forskolin activation. In our preparation, VIP did not influence basal adenylate cyclase activity or the stimulation by guanine nucleotides, cholera toxin, and pertussis toxin. VIP potently inhibited the enhancement of cyclic AMP formation by forskolin and completely antagonized the inhibitory effect of cholera toxin on forskolin activation. These results suggest that neuromodulatory effects of somatostatin, substance P, and VIP are mediated by the inhibitory as well as stimulatory guanine nucleotide proteins G-i and G-s coupled to an adenylate cyclase system.
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PMID:Peptidergic modulation of G-protein coupled cyclic-AMP accumulation in the rat caudate nucleus. 127 50

The effect of the neuropeptides substance P, neurokinin A and alpha-calcitonin gene-related peptide (CGRP) on human neutrophil granulocytes was investigated. Substance P induced secondary granule secretion at a concentration of 100 microM. CGRP induced a significant secretory response at 10 microM and thus appeared to be about 10 times more potent than substance P. Calcitonin and a fragment of CGRP, CGRP(8-37), had no effect on neutrophil degranulation. The chemotactic peptide antagonist BOC-MLP (100 microM) inhibited lactoferrin secretion mediated both by CGRP and chemotactic peptide FMLP almost completely, while secretion in response to tumour necrosis factor (TNF) was unaffected. Results from receptor binding studies showed that CGRP and N-formyl-methionyl-leucyl-phenylalanine (FMLP) do not compete for binding. This indicates that CGRP does not exert its effects by binding to the chemotactic peptide receptor. CGRP induced a rapid increase in the cytosolic-free calcium concentration and this increase was not, unlike that induced by FMLP, abolished by preincubation of the cells with pertussis toxin (1000 ng/ml). Therefore CGRP signal transduction in neutrophils appears to involve rapid changes in the cytosolic-free calcium concentration but not a pertussis toxin-sensitive G-protein. In summary, this is the first report to show that CGRP can directly activate neutrophil granulocytes, and this probably occurs via a cell surface receptor which is distinct from that of FMLP although both the CGRP and FMLP-mediated effects can be blocked by BOC-MLP.
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PMID:Calcitonin gene-related peptide (CGRP) activates human neutrophils--inhibition by chemotactic peptide antagonist BOC-MLP. 128 94

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

This study compared the effects of endothelin-1 (ET-1), ET-2 and ET-3 on the guinea pig field-stimulated ileum. All ETs (0.3-30 nM) caused graded inhibitions of nerve-mediated responses followed by sustained contractions. The rank order of potencies for the twitch depressor effect (IC50S) was ET-3 = ET-1 greater than ET-2, with ET-3 causing greater maximal inhibition than ET-1 or ET-2. The rank order of potencies for contraction (EC50S) was ET-1 = ET-2 greater than ET-3, with ET-1 causing greater maximal contraction than ET-2 or ET-3. Twitch inhibition by ET-1 (3 nM) was unaffected by indomethacin (5.6 microM), cromakalim (10 microM), glibenclamide (3 microM) or nicardipine (0.1 microM). ET-1-induced contraction was unaltered by tetrodotoxin (0.3 microM), atropine (0.3 microM) or glibenclamide, but was reduced by indomethacin. Cromakalim and nicardipine virtually abolished ET-1-induced contraction. ET-1 (up to 30 nM) did not potentiate submaximal contractions induced by acetylcholine, histamine, bradykinin or substance P. ET-3 relaxed ileal segments precontracted with either acetylcholine (0.3 microM) or histamine (1 microM). Pretreatment of guinea pigs with pertussis toxin (50 micrograms/kg i.p., 6 days beforehand) did not influence either effects of ET-1 on the field-stimulated ileum. Our data suggest that the dual effects of ETs on the guinea pig isolated ileum are mediated by distinct receptors and possibly involve different mechanisms of action. The transient inhibition of responses to field stimulation seems unrelated to activation of ATP-sensitive potassium channels and is rather insensitive to L-type Ca++ channel blockade.
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PMID:Dual effects of endothelins -1, -2 and -3 on guinea pig field-stimulated ileum: possible mediation by two receptors coupled to pertussis toxin-insensitive mechanisms. 137 59

It has been proposed that mastoparan (INLKALAALAKKIL) and other mast cell secretagogues such as substance P (SP) or compound 48/80 act by direct activation of the pertussis toxin (PTX)-sensitive G-proteins in intact cells. Here we have investigated whether or not the antagonists of SP, [D-Trp7,9,10] SP1-11 and [D-Trp7,9,10, N-leu11]SP1-11, can similarly induce exocytosis from RINm5F cells. In intact cells mastoparan and the SP antagonists stimulated insulin release in a dose-dependent manner at concentrations ranging from 10 to 100 microM. The maximal effect on insulin release, of both mastoparan and the SP antagonists was comparable to that obtained with 100 microM forskolin. Pretreatment of the intact cells, for 18 h with PTX or 6 h with cholera toxin, did not change the responses induced by both mastoparan and the SP antagonists. This absence of PTX effect, despite the fact that the three PTX substrates at 41, 40 and 39 kDa were ADP ribosylated after pretreatment suggests intrinsic differences between mast and RINm5F cells. Thus the SP antagonists behave similarly to mastoparan in its ability to induce insulin release in RINm5F cells. However, the higher concentrations required with RINm5F cells compared to that needed for mast cells suggest differences either in G-proteins composition or in the phospholipid composition of the membranes.
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PMID:Insulin releasing effects of mastoparan and amphiphilic substance P receptor antagonists on RINm5F insulinoma cells. 137 73

Using a perfused rat hindleg system, release of tissue-type plasminogen activator (t-PA) from endothelial cells could be induced by platelet-activating factor (PAF), bradykinin, substance P, thrombin, carbachol and A23187, while this release was inhibited by mepacrine and by nor-dihydroguaiaretic acid. The PAF-induced release of t-PA was inhibited by the cytochrome P-450 mono-oxygenase inhibitors, metyrapone, ketoconazole and SKF 525A and by eicosatetraynoic acid but not by indomethacin or BW 755C, suggesting the involvement of epoxygenase products. The PAF-induced release of von Willebrand factor (vWF) was also similarly inhibited by the cytochrome P-450 monooxygenase inhibitor, ketoconazole. Phorbol ester and phospholipase C induced the release of both t-PA and vWF, while phospholipase A2 did not. The release induced by PAF and bradykinin was not influenced by pretreatment with pertussis toxin.
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PMID:The involvement of products of the phospholipase pathway in the acute release of tissue-type plasminogen activator from perfused rat hindlegs. 152 62

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.
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PMID:Recombinant bovine neurokinin-2 receptor stably expressed in Chinese hamster ovary cells couples to multiple signal transduction pathways. 166 1

The effects of single intracerebroventricular (icv) injections of either 0.5 microgram pertussis toxin or 5 micrograms N-ethylmaleimide (NEM) on the levels of immunoreactive substance P (ir-SP) and serotonin (5-HT) in the brain and spinal cord of rats have been assessed. At two and six days after pertussis toxin injection, the levels of ir-SP appeared significantly diminished in the spinal cord (about 34%). This reduction was even greater at two days after NEM injection (43%). These two agents did not alter the ir-SP of the midbrain and thalamus, whereas NEM increased the neuropeptide content in the pons-medulla. On the other hand, the thalamic content of serotonin was reduced two days after pertussis toxin (32%) or NEM (20%) injection. The indoleamine levels of the spinal cord were reduced by these treatments (20%), while in the midbrain a slight decrease could be observed. These findings suggest that pertussis toxin and NEM produce these effects by acting upon a common neural substrate.
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PMID:Effect of ICV pertussis toxin and N-ethylmaleimide on the levels of substance P and serotonin in brain and spinal cord of the rat. 169 1

Bradykinin, kallidin (Lys-bradykinin) and [Thi 5,8, D-Phe7]-bradykinin, a functional B2 antagonist, induce histamine release from rat peritoneal mast cells. The histamine release is dependent upon added calcium when mast cells are placed in calcium-free medium 30 min before being triggered with the kinins. Histamine release was dose-dependently inhibited by pertussis toxin (1-100 ng/ml) and by benzalkonium chloride (0.1-3 micrograms/ml). The efficiency of ionophore A23187 on histamine release was affected neither by pertussis toxin nor by benzalkonium chloride. The parallel response of rat peritoneal mast cells to kinins and to substance P suggest that these peptides have the same mechanisms of action i.e. activation of a pertussis toxin-sensitive G protein and of phospholipase C defining a peptidergic triggering pathway of mast cells.
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PMID:A pertussis toxin-sensitive G protein is required to induce histamine release from rat peritoneal mast cells by bradykinin. 169 72

In enzymatically dispersed enriched (76%) rat parietal cells we studied the effect of substance P on acid sequestration as indirectly measured by [14C]aminopyrine accumulation. Substance P (10(-8)-10(-5) M) had no effect on basal [14C]aminopyrine accumulation. Yet, the peptide reduced the response to histamine and to the postreceptor agonists forskolin and dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP). Inhibition by substance P followed noncompetitive kinetics and reduced stimulated parietal cell function by up to 45% at 10(-5) M. The antagonist [D-Pro2, D-Trp7,9]-substance P at 10(-5) M partly reversed the inhibitory effect of substance P. Cholinergic stimulation of [14C]aminopyrine accumulation was not reduced by substance P. Neurokinin A, another tachykinin that is structurally related to substance P, was of comparable potency and efficacy in reducing [14C]aminopyrine accumulation in response to histamine, forskolin, and DBcAMP. Inhibition of forskolin- or DBcAMP-induced [14C]aminopyrine accumulation persisted in the presence of 10(-5) M ranitidine. Inhibition by substance P and neurokinin A of the response to histamine was not sensitive to pertussis toxin. Both tachykinins failed to reduce histamine- and forskolin-stimulated cAMP production. Our data suggest that substance P and neurokinin A exert a direct effect on rat parietal cells. They attenuate histamine-stimulated acid sequestration at an intracellular step that is distal to the adenylate cyclase and that does not involve pertussis toxin-sensitive GTP-binding proteins.
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PMID:Effect of substance P and neurokinin A on rat parietal cell function. 169 30


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