UNIPROT:P20366 - FACTA Search

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)

A novel ligand, [4,5-3H-Leu10]substance P ([3H]SP), with high specific activity (137 Ci/mmole) was utilized to investigate the properties of NK (neurokinin)-1 receptors on guinea pig lung membranes (GPLM) and compared them to NK-1 receptors on rat submaxillary glands (RSGM). In the presence of a neutral endopeptidase inhibitor, thiorphan (100 microM), [3H]SP bound with high specificity (greater than 95%), rapidly (k1 = 0.116 nM-1 x min-1) and in a reversible (k-1 = 0.012 min-1) manner to a single class of high-affinity (Kd = 0.16 nM) and saturable (Bmax = 256 fmol/mg protein) receptors. High specific binding with higher density (5-fold) was also detected in RSGM, albeit with a lower affinity (Kd = 1.36 nM). Guanyl-5'-yl-imidodiphosphate and guanosine-5'-O-3-thiotriphosphate inhibited binding to GPLM (and RSGM) in a concentration-related manner. In GPLM, this effect was mediated by a reduction in affinity, mainly via enhancement of ligand dissociation rates and appearance of a lower affinity state (Kd = 3.4 nM). Preincubation of GPLM with sulfhydryl modifying agents (p-chloromercuriphenyl sulfonic acid and N-ethylmaleimide) reduced receptor density and affinity in a time- and concentration-dependent manner. Competition experiments with tachykinins and analogs illustrated a rank order of potency of: SP greater than or equal to [Sar9,Met(O2)11]SP greater than SP-methyl ester greater than or equal to physalaemin greater than SP(6-11) much greater than kassinin greater than neurokinin A = eledoisin much greater than neurokinin B greater than Nle10-NKA(4-10), clearly demonstrating that these receptors are of NK-1 type. Moreover, analysis of over 30 peptide and non-peptide hormones and antagonists demonstrated exquisite selectivity (greater than 10,000-fold) towards NK-1-selective agonists (vs. other ligands. A highly significant (P less than .005) linear correlation (r = 0.924) exists between agonist affinities in GPLM and RSGM. Combined, the data suggest that [3H]SP labels a nearly homogeneous population of high-affinity, G-protein coupled NK-1 receptors on GPLM and RSGM, with very high degree of selectivity.
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PMID:Binding of the novel ligand [4,5-3H-Leu10]substance P to high-affinity NK-1 receptors on guinea pig lung membranes: modulation by GTP analogs and sulfhydryl modifying agents. 171 78

Arthroscopy was performed on 18 patients (19 joints) with temporomandibular joint arthropathy. Arthroscopic investigation revealed that 12 patients had disk derangement, including 3 patients with rheumatoid arthritis. Six patients had osteoarthrosis, including one patient with rheumatoid arthritis. Synovial fluid content of substance P-like immunoreactivity (SP-LI), neurokinin A (NKA-LI), calcitonin gene-related peptide (CGRP-LI), neuropeptide Y (NPY-LI) and vasoactive intestinal polypeptide (VIP-LI) were analysed using radioimmunoassay technique. All peptides analysed were found, although in various concentrations, in the different joints. There were no significant differences in concentrations of the peptides in the synovial fluid between patients in the various groups. No significant correlation was found between clinical symptoms and signs, arthroscopic findings, or use of analgesic/anti-inflammatory medication versus concentrations of peptides in the synovial fluid. In comparison with earlier findings in the knee joint significantly higher concentrations of SP-LI, CGRP-LI and NPY-LI were found in the TMJ.
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PMID:Concentrations of neuropeptides substance P, neurokinin A, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid of the human temporomandibular joint. A correlation with symptoms, signs and arthroscopic findings. 171 5

Substance P and a series of related neurokinins having various degrees of selectivity for tachykinin receptors have been studied for their effects on gastric acid secretion both "in vitro" and "in vivo". In the isolated gastric fundus from immature rats, substance P, the C-terminal heptapeptide of neurokinin A, NKA (4-10), [Arg]NKB and two synthetic analogues of NKA (4-10), namely, [beta-Ala8]NKA (4-10) and [Ala5]NKA (4-10) (compounds marked Men 10210 and Men 10209, respectively) had no effect on spontaneous secretion but enhanced the secretory response to histamine. All the different neurokinins were effective in the range of concentrations 10(-7) - 10(-6) M. In the conscious cat with gastric fistula, substance P dose-dependently increased basal acid secretion, whereas Men 10210 was absolutely ineffective. Men 10209 caused a slight increase in acid output which, however, was only 10% of that induced by dimaprit or pentagastrin. The secretory effect of dimaprit and pentagastrin was not affected by the different neurokinins, conversely the response to 2-Deoxy-D-glucose was slightly reduced by Men 10210 (10 nmol/kg/h). The above data suggest that the natural and synthetic neurokinins studied have negligible effects on gastric acid secretion, thus the gastro-protective effect observed in some experimental conditions is unlikely to be related to an antisecretory effect of these compounds.
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PMID:Effect of substance P and related neurokinins on gastric acid secretion. 171 76

The cutaneous nerves of rat, cat, guinea pig, pig, and man were studied by immunocytochemistry to compare the staining potency of general neural markers and to investigate the density of nerves containing peptides. Antiserum to protein gene product 9.5 (PGP 9.5) stained more nerves than antisera to neurofilaments, neuron-specific enolase (NSE), and synaptophysin or histochemistry for acetylcholinesterase (AChE). Peptidergic axons showed species variation in density of distribution and were most abundant in pig and fewest in man. However, the specific peptides in nerves innervating the various structures were consistent between species. Nerve fibers immunoreactive for calcitonin gene-related peptide (CGRP) and/or vasoactive intestinal polypeptide (VIP) predominated in all the species; those immunoreactive to tachykinins (substance P and neurokinin A [NKA]) and neuropeptide tyrosine (NPY) were less abundant. Neonatal capsaicin, at the doses employed in this study, destroyed approximately 70% of CGRP- and tachykinin-immunoreactive sensory axons; whereas 6-hydroxydopamine (6-OHDA) at the doses employed resulted in a complete loss of NPY and tyrosine hydroxylase (TH) immunoreactivity without affecting VIP, CGRP, and tachykinins. Thus, this study confirms that antiserum to PGP 9.5 is the most suitable and practical marker for the demonstration of cutaneous nerves. Species differences exist in the density of peptidergic innervation, but apparently not for specific peptides. Not all sensory axons immunoreactive for CGRP and substance P/NKA are capsaicin-sensitive. However, all sympathetic TH- and NPY-immunoreactive axons are totally responsive to 6-OHDA; but no change was seen in VIP-immunoreactive axons, suggesting some demarcation of cutaneous adrenergic and cholinergic sympathetic fibers.
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PMID:An immunocytochemical study of cutaneous innervation and the distribution of neuropeptides and protein gene product 9.5 in man and commonly employed laboratory animals. 171 91

The release of substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal infusion of histamine, methacholine, leukotriene D4, and platelet-activating factor was measured in isolated guinea pig lungs superfused through the trachea. Infusion of each of these agonists was associated with a significant (P less than 0.05) increase in the recovery of both SP-LI and NKA-LI from lung perfusates compared with preinfusion baseline recoveries of these peptides. After infusion of bronchoactive mediators, approximately 4-15 times more NKA-LI than SP-LI was recovered from the lung superfusate. Coincident with the release of neuropeptides, mediator infusion was accompanied by an increase in airway opening pressure (Pao). Addition to the perfusate of the neutral endopeptidase inhibitor thiorphan, 1 microM increased the change in Pao induced by histamine (10(-8) mol, P less than 0.005) and methacholine (10(-8) mol, P less than 0.02) and increased the recovery of NKA-LI (P less than 0.05 for histamine and methacholine). Addition of isoproterenol to the perfusion buffer reduced, but did not abolish, either the Pao response or the increased recovery of NKA-LI (P less than 0.05) observed after histamine infusion. We conclude that bronchoactive agonists have the capacity to release both SP-LI and NKA-LI, and we speculate that NKA contributes to the bronchomotor response observed in response to histamine or methacholine.
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PMID:Release of tachykinins by histamine, methacholine, PAF, LTD4, and substance P from guinea pig lungs. 172 49

To investigate the participation of neuropeptides present in the peripheral endings of primary afferent neurons in the inflammatory response, immunoreactive substance P (iSP), calcitonin gene-related peptide (iCGRP) and neurokinin A (iNKA) levels in the s.c. perfusate, and inflammatory response (edema and plasma protein extravasation) evoked in rat paw by noxious stimulation were determined. The effects of these peptides on plasma protein extravasation in the skin of the hind paw of mice were also examined with the pontamine sky blue protein labelling method. The following results were obtained. 1) Immersion of the rat hind paw for 30 min into hot water adjusted to 47 degrees C led to a marked increase in the release of iSP and iCGRP in the subcutaneous perfusate with the formation of thermal edema. 2) Mechanical stimulation (600 g, 10 min) to the hind paw or electrical stimulation of the saphenous and sciatic nerves (10 V, 2 Hz, 1msec duration, 10 min) evoked the increase of iSP release in the perfusate with plasma protein extravasation. 3) iNKA release was not affected by neither heat nor mechanical stimulation. 4) Intraplantar injection of SP, CGRP and NKA induced plasma protein extravasation, the order of potencies being SP greater than CGRP greater than NKA. The action of SP was antagonized by spantide, an SP antagonist. The injection of CGRP with SP produced a synergistic action on plasma protein extravasation. 5) Neonatal pretreatment with capsaicin, which is known to degenerate small-diameter primary afferent neurons, caused the decrease in amount of iSP and iCGRP released during noxious heat stimulation. 6) Pretreatment with Compound 48/80, or stem bromelain and emorphazone, or des-Arg9-[Leu8]-BK, inhibited the iSP release evoked by noxious heat stimulation. 7) Opioids such as morphine (mu-agonist) and ethylketocyclazocine (kappa agonist) inhibited the heat stimulus-evoked iSP release and thermal edema, and the inhibitory effects were antagonized by pretreatment with their antagonists. 8) Morphine or ethylketocyclazocine or [D-Ala2,D-Leu5]-enkephalin (delta-agonist) inhibited the release of iSP evoked by electrical stimulation of the saphenous and sciatic nerves. These results indicate that SP and CGRP present in peripheral endings of small-diameter primary afferent neurons play an important role in the inflammatory response, and that opioids are involved in the regulation of inflammatory response through the inhibition of SP release.
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PMID:[A pharmacological study of the participation of the peripheral endings of primary afferent neurons in the inflammatory response evoked by heat and mechanical noxious stimulation]. 172 88

We have determined the ability of [beta Ala8]-NKA(4-10), a selective agonist for NK-2 tachykinin receptors to stimulate micturition in anesthetized rats and guinea-pigs. In both species, the intravesical instillation of the peptide at microM concentrations reduced bladder capacity and residual volume, indicating a facilitatory effect on reflex micturition. At these concentrations, no plasma extravasation was produced as determined by the Evans blue content of the organ. In experiments on the isolated rat or guinea-pig bladder strips, the NK-2 receptor agonist induced powerful contractions. In a in vitro model of the guinea-pig whole bladder the intravesical instillation of the NK-2 agonist facilitated the occurrence of rhythmic contractile activity. It is concluded from these studies that intravenous administration of [beta Ala8]-NKA(4-10) exerts a facilitatory effect on the micturition reflex, presumably involving the ability of the NK-2 receptor agonist to cross the urothelium and stimulate smooth muscle contraction.
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PMID:Facilitation of reflex micturition by intravesical administration of [beta Ala8]-neurokinin A (4-10), a selective NK-2 tachykinin receptor agonist. 184 72

Membranes isolated from a murine fibroblast B82 cell line (SKLKB82#3) transfected with the bovine stomach cDNA pSKR56S exhibited binding of [His(125I)1]neurokinin A (125I-NKA) to a single population of sites with a Bmax of 147 fmol/mg of protein and a Kd of 0.59 nM. Control cell lines had little or no specific binding. The ligand binding in SKLKB82#3 cells was reversible and was inhibited by peptides in the potency rank of neuropeptide gamma greater than neuropeptide K greater than neurokinin A greater than [10-norleucine]neurokinin A-(4-10) greater than substance P much greater than senktide (succinyl-Asp-Phe-MePhe-Gly-Leu-Met-NH2). Specific binding was enhanced by Mn2+, Mg2+, and Ca2+ and was inhibited by guanine nucleotide analogues. Thus, SKLKB82#3 cells have been transfected with NK2 receptors that have become associated with an endogenous guanine nucleotide-binding protein. In comparison with membranes from the hamster urinary bladder, a tissue enriched in NK2 receptors, NK2 receptor antagonists displayed markedly different potencies, either more or less potent, in inhibiting specific binding in membranes of the transfected cells. Furthermore, inhibition of 125I-NKA binding by nucleotide analogues was markedly different in SKLKB82#3 cells compared with hamster bladder tissue. The different binding profile in the cells is not due to an artefact introduced during cDNA transfection because a similar profile was also observed in bovine stomach membranes. These results may indicate the existence of two distinct NK2 receptors.
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PMID:Characterization of a tachykinin peptide NK2 receptor transfected into murine fibroblast B82 cells. 184 6

Tachykinins and CGRP label two distinct populations of neurons innervating the digestive system: intrinsic and extrinsic, afferents. The bulk of SP/tachykinin innervation originates from intrinsic neurons, even though a minor component of this innervation derives from afferent neurons, which are mostly located in dorsal root ganglia. Afferent SP/tachykinin fibers are mainly confined to a perivascular location and to the submocosa in the gut, but are distributed also to the hepatobiliary pathway and pancreas. On the contrary, the extrinsic CGRP-containing afferents form a major component of the sensory innervation of the alimentary tract, including the rich CGRP innervation of the esophagus, stomach, hepatobiliary tract, pancreas, and vasculature, as well as a portion of non-vascular fibers distributed to the intestinal wall. Tachykinin and CGRP immunoreactivities appear to be colocalized in a population of nerve fibers, which are likely to be extrinsic, afferent, since colocalization of these peptide immunoreactivities has not been reported in intrinsic neurons. The presence of SP/NKA-encoding transcripts in the enteric nervous system and sensory ganglia and the lack of hybridization signal with RNA probes complementary to NKB mRNA indicate that the PPT I gene, but not the PPT II gene, is transcribed in these structures. This observation, along with receptor binding sites and radioimmunoassay data, which have failed to detect NKB receptor binding sites or immunoreactivity (Eysselein et al., 1990; Maggio, 1988; Mantyh et al., 1988; 1989) in the intestine of several mammals, is consistent with a differential expression of the two PPT genes in the periphery and in the central nervous system (Brecha et al., 1989; Warden and Young, 1988). A differential expression of the tachykinin-encoding genes, the existence of multiple tachykinin receptor subtypes (Mantyh et al., 1988; 1989), and the findings that tachykinins can be differentiated on the basis of the potency of their activities (Galligan et al., 1987; Maggio, 1988), support the possibility that each tachykinin is expressed in separate, and perhaps functionally distinct neuronal systems. alpha- and beta-CGRP genes also are differentially expressed according to the neuronal populations: alpha-CGRP mRNA is the most prominent form in sensory ganglia, and beta-CGRP mRNA is the only form detected in enteric neurons (Mulderry et al., 1988; Sternini and Anderson, 1990). In addition, distinct distributions of mRNAs generated from the two CGRP genes have been reported in the central nervous system (Amara et al., 1985). The differential expression patterns of alpha- and beta-CGRP mRNAs are consistent with a differential regulation of the alpha- and beta-CGRP genes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Tachykinin and calcitonin gene-related peptide immunoreactivities and mRNAs in the mammalian enteric nervous system and sensory ganglia. 195 Jul 91

Peritonitis induced by serosal application of 0.1 M hydrochloric acid causes net fluid secretion via the enteric nervous system. The aim of the present study was to investigate the roles of vasoactive intestinal peptide (VIP) and tachykinins in this reflex(es). The release of tachykinins (substance P [SP], neurokinin A [NKA], neuropeptide K [NPK]) and VIP into the mesenteric circulation, net fluid transport, intestinal blood flow and sometimes motility were recorded simultaneously in extrinsically denervated jejunal segments of the cat in vivo. The release of both VIP and NKA was increased upon application of HCl to the cat jejunal serosa. Tetrodotoxin, hexamethonium and methionine enkephalin inhibited both the induced VIP release and the secretory response. The increased release of NKA was unaffected by hexamethonium. We propose that the intramural secretory reflex evoked by acid application of the serosa consists of an 'afferent' tachykinin neuron, a cholinergic interneuron and an 'efferent' VIPergic neuron innervating the secretory enterocytes.
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PMID:On the role of vasoactive intestinal polypeptide and tachykinins in the secretory reflex elicited by chemical peritonitis in the cat small intestine. 197 7

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