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 mammalian tachykinin neuropeptides substance P (SP) and neurokinin A (NKA) are present in the airways of several species and are involved in control of bronchomotor tone. We investigated the effect of SP and NKA on various respiratory and cardiovascular parameters in anaesthetized sheep. Dose-dependent decrease in dynamic compliance (Cdyn) and increase in respiratory resistance (RL) occurred with intravenous administration of SP. The predominant effect of NKA was on Cdyn with little or no effect on RL. Consequently SP is a more potent bronchoconstrictor than NKA in the sheep and affects both central and peripheral airway tone. The sensitivity to SP and NKA and the order of potency found suggests the NK-1 receptor predominates in sheep airways. Atropine and the ganglion blocker hexamethonium markedly reduced the bronchoconstriction caused by SP. SP and NKA were equipotent in causing a significant reduction in respiratory rate. SP caused a fall in mean blood pressure while NKA caused mild vasoconstriction. Neither peptide affected heart rate. We concluded that SP is a more potent bronchoconstrictor than NKA in the sheep and that the mechanism of action is mainly indirect involving modulation of postganglionic cholinergic nerve endings.
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PMID:The effect of tachykinins on sheep bronchomotor tone. 137 45

The tachykinins are a group of structurally related peptides found in the rat hypothalamus and anterior pituitary. We have evaluated the effects of four tachykinins on LH release in male rats. In intact male rats, intracerebroventricular (icv) injection of neurokinin A (NKA), neuropeptide K (NPK), and neuropeptide-gamma (NP gamma) elicited dose-related, transient increases in plasma LH. Substance P (SP) was ineffective under these conditions. A further examination showed that in vitro incubation with either NPK or NP gamma of hemipituitaries from intact but not castrated male rats promoted release of LH into the medium, thereby revealing that the excitatory effects of tachykinins in intact male rats may, in part, be a result of stimulation of LH release directly from the anterior pituitary. On the other hand, the effects of these four tachykinins on LH release were different in castrated rats. Intracerebroventricular injection of NPK, NKA, and NP gamma as well as SP, which was ineffective in intact male rats, evoked a long-lasting suppression of LH release. Comparatively, NPK was the most effective tachykinin in eliciting LH responses in both of these tests involving different endocrine environments. We next evaluated the possibility that the inhibitory effects of tachykinins (NPK) may be mediated by activation of inhibitory endogenous opioid peptides. The results showed that iv infusion of the opiate receptor antagonist naloxone, to block the possible inhibitory effects of endogenous opioid peptides, only partially counteracted the suppressive effects of icv NPK on plasma LH levels. Thus, in addition to revealing the diverse effects of structurally related tachykinins on LH release, the results of these investigations showed specifically that the NK-2 receptor agonists NPK, NP gamma, and NKA stimulated LH release in intact rats, in part, by a direct action at the level of the pituitary, whereas the NK-1 receptor agonist SP was inactive under these conditions. These findings imply a paracrine/autocrine mode of excitatory action on LH release involving pituitary NK-2 receptor subtypes. On the other hand, in castrated rats, all four tachykinins readily suppressed LH release by a central action involving, in part, an activation of hypothalamic opioid systems.
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PMID:Diverse effects of tachykinins on luteinizing hormone release in male rats: mechanism of action. 138 Apr 35

WS9326A binds competitively to [3H]substance P (NK-1 receptor) binding sites on guinea-pig lung membranes (IC50 = 3.6 x 10(-6) M), and acts as a tachykinin antagonist in various functional assays. WS9326A inhibited tracheal constrictions produced by exogenously added substance P and neurokinin A, with IC50 values of 9.7 x 10(-6) M and 3.5 x 10(-6) M, respectively. WS9326A inhibited neurokinin A-induced bronchoconstriction in a dose dependent manner when administered to guinea-pigs intravenously together with neurokinin A, and was also effective in preventing capsaicin-induced bronchoconstriction, which is known to be caused by release of endogenous tachykinins (substance P and neurokinin A). FK224 (tetrahydro-WS9326A; catalytic hydrogenation of WS9326A gave FK224) was more potent than WS9326A in the [3H]substance P receptor binding assay using guinea-pig lung membrane (IC50 = 1.0 x 10(-7) M).
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PMID:WS9326A, a novel tachykinin antagonist isolated from Streptomyces violaceusniger no. 9326. II. Biological and pharmacological properties of WS9326A and tetrahydro-WS9326A (FK224) 138 44

We examined the direct effect of motilin on longitudinal and circular smooth muscle cells isolated from the guinea pig small intestine. In addition, the effects of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride (TMB-8, an inhibitor of intracellular Ca(2+)-release), verapamil (a voltage-dependent Ca(2+)-channel blocker), and removal of extracellular Ca2+ were investigated to evaluate the role of intracellular Ca2+ stores and extracellular Ca2+ on the muscle contraction induced by motilin. The effects of atropine (a muscarinic receptor antagonist), spantide (a substance P receptor antagonist) and loxiglumide (a CCK-receptor antagonist) were also examined to determine whether the motilin-induced contraction was independent of those receptors. Motilin induced a contraction of the longitudinal and circular smooth muscle cells in a dose-dependent manner with the maximal effect attained after 30 seconds of incubation. The ED50 values were 0.3 nM and 0.05 nM, respectively. TMB-8 suppressed completely the motilin-induced contraction of both types of smooth muscle cells. Verapamil had only a slight suppressive effect. Removal of extracellular Ca2+ did not have any significant influence on motilin-induced contraction. The contractile response to motilin was not affected by atropine, spantide or loxiglumide. Our findings showed that:1) motilin has a direct contractile effect on both longitudinal and circular smooth muscle cells; 2) this contractile effect is not evoked via muscarinic, substance P or CCK receptors, and 3) the intracellular release of Ca2+ plays an important role in the contractile response to motilin on both types of smooth muscle cells.
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PMID:Direct contractile effect of motilin on isolated smooth muscle cells of guinea pig small intestine. 138 65

[D-Arg1, D-Trp7,9, Leu11]-substance P (spantide) was tested for antagonism against the licking, biting and scratching response induced by various neurokinin (NK) receptor agonists and bombesin (Bom) in mice. When co-administered with substance P (SP) intrathecally, spantide reduced the SP-induced behavioural responses in a dose-dependent manner. The duration of this antagonistic effect was approximately 30 min. Behavioural responses induced by physalaemin (Phy), [pGlu6, L-Pro9]-SP (6-11) (septide), [pGlu6, D-Pro7]-SP (6-11) (D-septide) and eledoisin (Ele) were also dose-dependently decreased by relatively small doses of spantide. Higher doses of spantide were needed to reduce the behavioural responses induced by [Sar9, Met (O2)11]-SP, neurokinin A (NK A) and neurokinin B (NK B). No significant effect of spantide was observed against the behavioural responses elicited by Bom. Pretreatment with naloxone, an opioid antagonist, resulted in a reversible effect on the behavioural reduction of NK-2 and NK-3 receptor agonists produced by spantide. However, the effect of spantide on the NK-1 receptor agonist-induced response was unchanged by naloxone. In homogenates of mouse spinal cord, competition studies confirmed that the binding of the opioid ligand [3H]naloxone was displaced by spantide with a low but measurable affinity. These results suggest that the behavioural response to NK-2 and NK-3 receptor agonists may be partially inhibited by spantide through the activation of opioid system in the mouse spinal cord.
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PMID:Naloxone-reversible effect of spantide on the spinally mediated behavioural response induced by neurokinin-2 and -3 receptor agonists. 138 32

The nonpeptide substance P receptor antagonist CP-96,345 was found to displace binding to Ca2+ channel binding sites labelled with either [3H]desmethoxyverapamil or [3H]diltiazem and to enhance [3H]nitrendipine binding. Unlike the substance P receptor antagonist activity of CP-96,345, these effects on Ca2+ channel binding sites were neither stereoselective nor species-dependent. It is concluded that CP-96,345 may act as an antagonist of L-type Ca2+ channels in addition to being a potent NK1 receptor (substance P) antagonist.
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PMID:The substance P receptor antagonist CP-96,345 interacts with Ca2+ channels. 138 77

Stromelysin-1 is a member of a tissue metalloproteinase family whose members are all capable of degrading extracellular matrix components. A truncated form of human fibroblast prostromelysin 1 lacking the C-terminal, hemopexin-like domain has been expressed in Escherichia coli and purified to homogeneity. Treatment of this short form of prostromelysin with (aminophenyl)mercuric acetate resulted in activation and loss of the propeptide in a manner identical with the wild-type, full-length protein. Kinetic comparisons using Nle11-substance P as a substrate showed that the wild-type stromelysin and the truncated form of the enzyme had similar kcat and Km values. Likewise, both enzymes displayed similar Ki values for a hydroxamate-containing peptide inhibitor. Taken together, these results indicate that the C-terminal portion of stromelysin is not required for proper folding of the catalytic domain, maintenance of the enzyme in a latent form, activation with an organomercurial, cleavage of a peptide substrate, or interaction with an inhibitor. Moreover, the active short form of stromelysin displayed a reduction in the C-terminal heterogeneity, a characteristic degradation of the full-length stromelysin, and thereby provides a more suitable protein for future structural studies.
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PMID:Human fibroblast stromelysin catalytic domain: expression, purification, and characterization of a C-terminally truncated form. 164 1

The gene for the human substance P receptor (NK-1) was cloned using cDNA probes made by the polymerase chain reaction from primers based on the rat sequence. The gene spans 45-60 kb and is contained in five exons, with introns interrupting at sites homologous to those in the NK-2 receptor gene. Analysis of restriction digests of genomic DNA from mouse/human cell hybrids indicates the NK-1 receptor is a single-copy gene located on human chromosome 2. Polymerase chain reaction using primers based on the 5' and 3' ends of the coding sequence was used to generate full-length cDNAs from human lung and from IM9 lymphoblast cells. When transfected into COS-7 cells, the NK-1 receptor binds 125I-BHSP with a Kd of 0.35 +/- 0.07 nM and mediates substance P induced phosphatidylinositol metabolism. The receptor is selective for substance P; the relative affinity for neurokinin A and neurokinin B is 100- and 500-fold lower, respectively. Human IM9 lymphoblast cells express relatively high levels of the NK-1 receptor, and Northern blot analysis indicates modulation of mRNA levels by glucocorticoids and growth factors, suggesting that this cell line may be useful as a model for studying the control of NK-1 receptor gene expression.
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PMID:Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. 165 50

Neurokinin-1 (NK-1)/substance P (SP) receptors were solubilized using 10 mM 3-[( cholamidopropyl)-dimethylammonio]-1- propanesulfate from porcine striatal membranes (solubilization yield, 80%). In solubilized preparations, [3H]SP apparently bound to a single class of high-affinity sites (KD = 0.82 +/- 0.13 nM) as in membrane homogenates. The ligand selectivity pattern observed in both membrane and solubilized receptor preparations indicated that [Sar9,Met(O2)11]SP = SP much greater than senktide = [Nle10]neurokinin A. This suggests the selective labeling of the NK-1 receptor class in both assays. Solubilized receptors were retained on agarose-coupled lectins that bind N-acetylglucosamine-galactose and beta-galactose (Ricinus communis I and Ricinus communis II), mannose (concanavalin A and lentil), and N-acetylglucosamine (wheat germ agglutinin) but not on lectins binding fucose (Lotus A) and N-acetylgalactosamine (Doli-chos biflorus A). Thus, it appears that porcine brain NK-1/SP receptors are enriched with various carbohydrate moieties, beta-galactose and N-acetylglucosamine-galactose residues being especially abundant. This situation is rather different from that in various other members of the rhodopsin seven-transmembrane receptor superfamily.
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PMID:Presence of various carbohydrate moieties including beta-galactose and N-acetylglucosamine residues on solubilized porcine brain neurokinin-1/substance P receptors. 165 28

Functional cDNA clones for human NK-1 receptor were isolated from human lung RNA using the polymerase chain reaction (PCR). We have screened a human cosmid library and isolated a clone which appeared to contain the entire NK-1 receptor gene. From the published rat NK-1 receptor cDNA sequence we designed primers within the protein coding sequence, but outwards towards both the 5' and 3' ends of the putative human protein sequence. By this method we derived DNA sequence from the 3' end of the human gene. In order to determine the 5' end of the gene we used a PCR based method called Rapid Amplification of cDNA Ends (RACE). From the derived human sequences amplimers were designed upstream of the ATG initiation codon and downstream of the stop codon. The entire cDNA was obtained by RNA-PCR from human lung RNA. The sequence obtained was 407 amino acids in length, encoding an open-reading frame that was highly homologous to the rat NK-1 receptor cDNA (89%). The entire human cDNA was then cloned into a mammalian expression vector and mRNA was synthesized by in vitro transcription. Applications of tachykinins caused membrane current responses in Xenopus oocytes injected with the in vitro synthesized mRNA. The most potent of the three tachykinin peptides tested was Substance P. The human NK-1 receptor gene has been mapped to chromosome 2 using the polymerase chain reaction to specifically amplify the human sequence in hamster/human hybrid DNA and also in mouse/human monochromosome hybrids.
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PMID:Isolation and characterisation of the human lung NK-1 receptor cDNA. 131 75


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