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)

Although abundant evidence suggests a major role for substance P (SP) and other neurokinins (NK) in the transmission of nociceptive information, it is not known whether the various NK receptor classes are differentially located in the substantia gelatinosa of the spinal cord where primary afferent fibres mostly terminate. In order to investigate this issue, we studied the effects of unilateral dorsal rhizotomy on binding of 125I-Bolton-Hunter-SP, (2-[125I]iodohistidyl1)-neurokinin A, and 125I-Bolton-Hunter-eledoisin as respective radioligands for the NK-1, NK-2 and NK-3 receptor sub-types. Seven, 14, 21 and 28 days following unilateral lumbosacral dorsal horn deafferentiation, NK receptor binding parameters were evaluated using quantitative receptor autoradiography. Rhizotomy produced an increase in the densities of NK-1, NK-2 and NK-3 binding sites in the superficial laminae of the dorsal horn. Increases were maximal at 14 days, post-operatively, for both NK-1 and NK-2 sites; slight recovery being observed thereafter. For NK-3 sites, unilateral rhizotomy induced a progressive increase in binding without evidence of recovery over time, at least up to 28 days post-lesion. NK-1 receptor binding parameters around the central canal and in the ventral horn were not affected by the dorsal rhizotomy. These data suggest that all 3 NK receptor classes are located post-synaptically to afferent fiber terminals in laminae I, II and X of the dorsal horn of the spinal cord.
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PMID:Effects of dorsal rhizotomy on neurokinin receptor sub-types in the rat spinal cord: a quantitative autoradiographic study. 171 14

The aim of the study was to assess which tachykinin receptors mediate the contractile response in the guinea-pig isolated bronchi. Experiments with natural tachykinins and receptor-selective tachykinin agonists were performed in the absence or presence of peptidase inhibitors and in bronchi pretreated with phenoxybenzamine. Both NK-1 (substance P, substance P methylester and septide) and NK-2 (neurokinin A, [beta-Ala8]neurokinin A-(4-10) and MDL 28,564) receptor agonists produced concentration-dependent contraction. NK-3 agonists (senktide and [MePhe7]neurokinin B) were active only at high concentrations. Phenoxybenzamine pretreatment reduced the maximal response to NK-1 agonists and produced a rightward shift of the curve to NK-2 agonists, without depression of the maximum. Five tachykinin antagonists selective for the NK-1 (L 668,169) or the NK-2 (MEN 10,207, MEN 10,376, L 659,877 and R 396) receptor were tested against substance P methylester and [beta-Ala8]neurokinin A-(4-10). The results indicated that these receptor-selective antagonists maintain their characteristic even when tested in a multireceptor assay such as the guinea-pig bronchus. The rank order of potency of NK-2 antagonists against [beta-Ala8]neurokinin A-(4-10) was MEN 10,207 = MEN 10,376 greater than L 659,877 much greater than R 396. This pattern, with the observation of the full agonist activity of MDL 28,564, indicates that in addition to NK-1 receptors, NK-2 receptors also are present in the guinea-pig bronchi and belong to the same subtype (NK-2A) as present in the rabbit pulmonary artery.
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PMID:Tachykinin receptors in the guinea-pig isolated bronchi. 171 90

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

The D-enantiomer of residues 2, 4, 5, 6, 7, 8, 10 and 11 was introduced in the sequence of Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. The achiral glycine residue was replaced by a D-Ala residue. Regarding NK-1 binding potencies or activities, changing to the D-enantiomer in positions 2, 4 or 5 did not modify the pharmacological patterns of the resulting peptides. Introduction of a D-residue in the 6 to 11 sequence drastically decreased the potency of the D-analogues with the exception of [D-Leu10]SP which was found only three times less potent than SP in contracting the guinea-pig ileum. No clear cut evidence between the binding potencies and activities on NK-1, NK-2 and NK-3 assays, was observed which allows a more rational design of tachykinins antagonists.
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PMID:Influence of the replacement of amino acid by its D-enantiomer in the sequence of substance P. 1. Binding and pharmacological data. 171 76

The neurokinins are a group of naturally occurring peptides with the common C-terminal sequence Phe-X-Gly-Leu-Met.NH2. They include substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). SP and NKA are coded on the same gene, the PPT-A, while NKB is coded on a separate gene, the PPT-B. Neurokinins are present in the central nervous system and in peripheral organs where they exert various actions. They act on three receptors--NK-1, NK-2, and NK-3--characterized through pharmacological, biochemical, and histochemical studies. Selective agonists for each neurokinin receptor were developed and evaluated on isolated smooth muscle preparations containing only one neurokinin receptor type. All three neurokinin receptors were cloned and expressed in Xenopus oocytes. Relative affinities of those receptors to neurokinins are the same as in their respective smooth muscle preparation. Finally, the mechanism of action of SP on histamine release from rat peritoneal mast cell has been studied and a direct activation of G proteins by peptides with basic amino acids is proposed as a working hypothesis.
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PMID:Pharmacology of neurokinin receptors. 171 74

Four neurokinin antagonists of different size have been used to counteract the myotropic effects of substance P, neurokinin A and neurokinin B in isolated organs containing a single receptor type (monoreceptor systems). These are: the dog carotid artery, the rabbit jugular and cava veins and the guinea pig ileum (NK-1), the rabbit pulmonary artery (NK-2) and the rat portal vein (NK-3). Undeca and octapeptides containing 2 D-Trp residues in their sequences were slightly more active on the NK-1, than on the NK-2 and NK-3 receptors and showed little selectivity. In contrast, compound AcThr-D.Trp(For)-Phe.NMe Bz was found to be as good an antagonist as the larger compounds and showed some selectivity for the NK-1 receptors. When tested against kinins or angiotensin, all compounds were found to be inactive, suggesting that they are specific for neurokinins. The present results show that NK-1 receptor antagonism can be obtained with compounds of different size, including tripeptides and nonpeptides.
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PMID:Neurokinin receptors antagonists: old and new. 171 24

This study investigated the subtype and coupling mechanisms mediating the direct contractile response to tachykinins in the guinea-pig Taenia caeci preparation in vitro. Coupling of neurokinin receptors was compared throughout with coupling of muscarinic receptors. The smooth muscle neurokinin receptors seem to be predominantly of the NK-1 subtype. Thus, the relative activities of the common naturally-occurring tachykinins fell within one order of magnitude, and the selective NK-1 receptor agonist substance P methyl ester was high in activity (0.38 relative to substance P). Some contribution from NK-3 receptors is, however, possible in view of the appreciable activity of the selective NK-3 agonist succ-[Asp6, N-MePhe8]-SP(6-11) (senktide; activity 0.004 relative to substance P), and NK-2 or NK-3 receptors in view of the higher activity of the D-isomer of [Glp6, *Pro9]-SP(6-11) as compared to its NK-1 selective L-isomer (D/L-activity ratio 1.53). Contractile actions of tachykinins were compared with carbachol for reliance on membrane-potential dependent (electromechanical) and membrane-potential independent (pharmacomechanical) coupling mechanisms. Log concentration-response curves to carbachol and substance P in normal Krebs' medium were compared with curves obtained in a high-K+ solution where processes dependent on changes in membrane potential could play no part in excitation. In the high-K+ depolarizing solution, a concentration-related relationship was maintained, though with some diminution in the maximal additional tension generated: the maximum tension with carbachol was under both conditions greater than that with substance P. The relative effects of several tachykinins and carbachol in producing receptor-mediated changes in membrane permeability through presumed receptor-operated ion channel opening, was estimated in terms of the ability to increase 86Rb-efflux, as a marker for K+, in a high-K+ depolarizing solution. Carbachol (10 microM) consistently increased 86Rb-efflux. In contrast, no permeability increase could be detected with any tachykinin tested (substance P, eledoisin, substance P methyl ester, neurokinin A, neurokinin B, 1 or 10 microM). Tachykinins and carbachol were compared in terms of ability to increase phosphatidylinositol hydrolysis. Both substance P and carbachol showed a concentration-related increase in accumulation of total inositol phosphates; though the maximal response to carbachol was considerably greater than that to any tachykinin (substance P, eledoisin, substance P methyl ester, senktide, neurokinin A, neurokinin B), or combination of two tachykinins (substance P and eledoisin, senktide and substance P methyl ester).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Subtypes and excitation-contraction coupling mechanisms for neurokinin receptors in smooth muscle of the guinea-pig Taenia caeci. 171 34

Angiotensin II, bradykinin, and substance P are powerful vasoconstrictors of venous smooth muscle. In this report, we have characterized the receptors and the cellular mechanisms of these vasoactive peptides on a new isolated smooth muscle preparation, the rabbit vena cava. Receptors were characterized using agonists and antagonists and were found to be of the AT, B2, and NK-1 types. The myotropic responses of the vein to KCl was completely abolished in calcium-free medium; in the presence of nicardipine, nifedipine, and verapamil, three calcium channel antagonists; and of trifluoperazine, a calmodulin antagonist. AT II-, BK-, and SP-induced responses were slightly attenuated in calcium-free medium and in the presence of nifedipine and trifluoperazine. Pinacidil inhibited the contractile response of KCl and the three peptides while lidocaine was active against KCl only. Staurosporine and cholera toxin strongly inhibited the contractile responses of the vein to AT II, BK, SP, and KCl, probably by a nonspecific effect. It is concluded that AT II-, BK-, and SP-induced contractions of the rabbit vena cava are mediated by specific receptors and in part by an influx of extracellular Ca2+ through dihydropyridine-insensitive channels. Opening of K+ channels and inhibition of the Ca(2+)-calmodulin complex appear to interfere with the smooth muscle response to the peptides.
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PMID:Pharmacological evaluation of the angiotensin, kinin, and neurokinin receptors on the rabbit vena cava. 172 Aug 40

The original proposal that substance P is involved in the regulation of nociceptive information at the first sensory synapse in the spinal cord has been substantiated by a wide range of evidence, but definitive support has been lacking, due primarily to the lack of evidence that a specific nociceptive response in the dorsal horn can be blocked by a substance P antagonist. Here, we present evidence that CP-96,345, a specific substance P (NK-1) receptor antagonist, selectively blocks a slow, prolonged excitatory postsynaptic potential following noxious cutaneous stimulation or a train of intense electrical stimuli to sensory nerves but does not affect the response to innocuous input or the brief response to single electrical stimuli to C fibers. These results indicate the specific involvement of substance P in the mediation of a prolonged after-excitation to noxious stimulation. This may have important implications for the etiology and treatment of chronic pain and for plastic changes in nociceptive pathways.
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PMID:Substance P-mediated slow excitatory postsynaptic potential elicited in dorsal horn neurons in vivo by noxious stimulation. 172 27

The effects of substance P, neurokinin A, neurokinin B, [Sar9, Met(O2)11]-substance P, [Nle10]-neurokinin A (4-10) and senktide (succinyl-[Asp6, MePhe8]-substance P (6-11)) on blood pressure and heart rate were studied in anesthetized dogs. Dose-dependent decreases in blood pressure and increases in heart rate were caused by each peptide except senktide. The latter elicited weak hypotensive or hypertensive responses at high doses. The order or potency was as follows: [Sar9, Met(O2)11]-substance P greater than or equal to substance P greater than neurokinin A greater than neurokinin B greater than [Nle10]-neurokinin A (4-10) much greater than senktide. CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner. Responses to each of the other peptides were inhibited by CP-96,345, 1.0 mg/kg (excluding senktide against which CP-96,345 was not tested). CP-96,344 (1.0 mg/kg i.v.) the 2R-3R enantiomer of CP-96,345 which does not block NK-1 receptors, had no effect on substance P-induced hypotension. We conclude that tachykinin-induced hypotension in dogs is mediated by NK-1 tachykinin receptors.
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PMID:Inhibition of tachykinin-induced hypotension in dogs by CP-96,345, a selective blocker of NK-1 receptors. 172 63


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