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)

Several neurokinins, namely substance P, neurokinin A, neurokinin B, [beta-Ala8]neurokinin A-(4-10) and senktide, were tested on noradrenaline-precontracted rabbit aortic rings to characterize the receptor mediating their endothelium-dependent relaxant effect in this preparation. CP-96,345, the new nonpeptide antagonist selective for the NK1 receptor, was also studied. Substance P, neurokinin A and neurokinin B, in that order of potency, were effective in relaxing precontracted rings, indicating the involvement of the NK1 receptor; [beta-Ala8]neurokinin A-(4-10) and senktide, which are selective agonists for NK2 and NK3 receptors, respectively, had no significant relaxant effect. The relaxant effects of substance P, neurokinin A and neurokinin B were competitively antagonized by nanomolar concentrations of CP-96,345. These findings support the view that the NK1 receptor mediates the endothelium-dependent relaxant effect of the neurokinins in rabbit aorta.
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PMID:Endothelium-dependent relaxant effect of neurokinins on rabbit aorta is mediated by the NK1 receptor. 131 13

We have recently shown that (a) [125I-Tyr8]bradykinin (BK) recognized bradykinin binding sites in guinea pig epithelium membranes with a Kd value of 1.6 nM and a Bmax of 156 fmol/mg protein, and (b) B2 agonists and some B2 antagonists, such as D-Arg-[Hyp3,D-Phe7,Leu8]BK, inhibited this specific binding with a Ki value of 32 nM. In the present study, we have radioiodinated the B2 antagonist Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK and have performed a full characterization of the binding properties of this tracer in the same membrane preparation. Equilibrium experiments performed in the absence or presence of an excess of BK (10(-5) M) showed that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK specifically labelled two different sites. One of these is the same as the site labelled by [125I-Tyr8]BK, and this indicates that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK interacts specifically with kinin B2 receptors. Equilibrium experiment performed in the presence of an excess of BK (10(-5) M) indicated that specific binding of 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK to the second site is also saturable and Scatchard analysis showed that the site is of high affinity with a Kd of 16.8 nM and a Bmax of 2.08 pmol/mg protein. Surprisingly, unlabelled B2 agonists such as bradykinin, [Tyr8]BK, [Leu8]BK, [Hyp3,Tyr8(OMe)]BK, D-Arg-[Hyp3]BK and kallidin were found to be inactive on this second site. A series of B2 receptor antagonists, Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK, D-Arg-[Hyp3,D-Phe7,Leu8]BK, D-Arg-[Hyp3,Leu5,8,D-Phe7]BK, D-Arg-[Hyp3,Gly6,D-Phe7,Leu8]BK and D-Arg-[Hyp3,Thi5,8,D-Phe7]BK inhibited 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK binding with Ki values of 25.0, 20.9, 15.8, 64.6 and 6606.9 nM respectively. On the other hand, [Thi5,8,D-Phe7]BK did not interfere with 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK but was found to be a potent inhibitor of [125I-Tyr8]BK binding (Ki = 53.7 nM). As expected, B1 receptor agonists, antagonists and peptides non-related to BK such as substance P, neurokinin A, neurokinin B, angiotensin II, bombesin, vasopressin and the calcitonin gene related peptide were unable to compete with 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK. The results show that 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]BK is interacting with two distinct binding sites in the guinea pig epithelium: one is the well known bradykinin B2 receptor and the other is a new, non-characterized binding site that interacts exclusively with some bradykinin receptor antagonists.
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PMID:Characterization of a novel binding site for 125I-Tyr-D-Arg-[Hyp3,D-Phe7,Leu8]bradykinin on epithelial membranes of guinea pig ileum. 132 66

Receptor binding site(s) on the rat urinary bladder membranes were characterized using a biologically active analog of bombesin, [Tyr4,Leu14]bombesin, and a 50,000 x g total particulate preparation. The binding was specific, reversible, saturable, time- and concentration-dependent. A dissociation curve showed that both bombesin and neuromedin B equally displaced the radioligand in the first 10 min after saturation. From the rate constant of association K + 1 = 7.60 x 10(9) M-1 min-1, and the rate constant of dissociation k-1 = 0.050 min-1, the apparent equilibrium dissociation constant Kd = 6.57 +/- 1.09 pM was determined. A linear Scatchard plot of the specific binding of 125I-[Tyr4,Leu14]bombesin to the membranes revealed that the radioligand bound with high affinity, Kd = 6.38 +/- 0.86 pM, to a single class of sites (Bmax = 2.3 fmol/mg protein). The Hill coefficient of the same binding data was 1.05 +/- 0.21, indicating that the radioligand was binding to a single population of noninteracting binding sites. Both bombesin and neuromedin B displaced the radioligand dose dependently (IC50 = 0.3 nM). Neurokinin A and neurokinin B were less potent (IC50 = 20 and 110 nM, respectively). Substance P, or the specific bombesin receptor antagonists [D-Phe6]bombesin-(6-13) methyl ester, [D-F5Phe6,D-Ala11]bombesin-(6-11) methyl ester, [D-Phe6]bombesin-(6-13) propylamide, [D-Phe6,Leu13psi(CH2NH)Leu14]bombesin or [D-Cpa6,Phe14(psi13-14)]bombesin-(6-14) had an IC50 greater than 1 microM. The results presented suggest the presence of neuromedin B receptor sites on the rat urinary bladder membranes that can be occupied also by some other peptides, notably bombesin, neurokinin A and neurokinin B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification and initial characterization of a putative neuromedin B-type receptor from rat urinary bladder membranes. 132 32

CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.
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PMID:Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist. 133 May 89

A tachykinin peptide was isolated from an extract of the intestine of the European green frog, Rana ridibunda, and its primary structure was established as: His-Lys-Leu-Asp-Ser-Phe-Ile-Gly-Leu-Met.CONH2. This sequence was confirmed by chemical synthesis and shows two amino acid substitutions (leucine for threonine at position 3 and isoleucine for valine at position 7) compared with neurokinin A. Binding parameters for synthetic [Leu3,Ile7]neurokinin A and mammalian tachykinins were compared using receptor-selective radioligands and crude membranes from tissues enriched in the NK1, NK2 and NK3 receptors. [Leu3,Ile7]Neurokinin A was approx. 3-fold less potent than substance P in inhibiting the binding of 125I-labelled [Sar9,Met(O2)11]substance P (labelled with Bolton-Hunter reagent) to rat submandibular gland (NK1 receptor), 8-fold less potent than neurokinin A in inhibiting the binding of [2-[125I]iodohistidine1]neurokinin A to rat stomach fundus (NK2 receptor) and 6-fold less potent than neurokinin B in inhibiting the binding of 125I-Bolton-Hunter-labelled scyliorhinin II to rat brain (NK3 receptor). Thus the frog neurokinin A-related peptide shows moderate affinity but lack of selectivity for all three tachykinin-binding sites in rat tissues. This non-selectivity is similar to that displayed by the molluscan tachykinin, eledoisin, which also contains an isoleucine residue in the corresponding position in the molecule.
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PMID:Primary structure and receptor-binding properties of a neurokinin A-related peptide from frog gut. 133 83

The chemical messengers released onto second-order dorsal horn neurons from the spinal terminals of contraction-activated group III and IV muscle afferents have not been identified. One candidate is the tachykinin substance P. Related to substance P are two other tachykinins, neurokinin A (NKA) and neurokinin B (NKB), which, like substance P, have been isolated in the dorsal horn of the spinal cord and have receptors there. Whether NKA or NKB plays a transmitter/modulator role in the spinal processing of the exercise pressor reflex is unknown. Therefore, we tested the following hypotheses. After the intrathecal injection of a highly selective NK-1 (substance P) receptor antagonist onto the lumbosacral spinal cord, the reflex pressor and ventilatory responses to static muscular contraction will be attenuated. Likewise, after the intrathecal injection either of an NK-2 (NKA) receptor antagonist or an NK-3 (NKB) receptor antagonist onto the lumbrosacral spinal cord, the reflex pressor and ventilatory responses to static contraction will be attenuated. We found that, 10 min after the intrathecal injection of 100 micrograms of the NK-1 receptor antagonist, the pressor and ventilatory responses to contraction were significantly (P < 0.05) attenuated. Mean arterial pressure was attenuated by 13 +/- 3 mmHg (48%) and minute volume of ventilation by 120 +/- 38 ml/min (34%). The cardiovascular and ventilatory responses to contraction before either 100 micrograms of the NK-2 receptor antagonist or 100 micrograms of the NK-3 receptor antagonist were not different (P > 0.05) from those after the NK-2 or the NK-3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Attenuation of reflex pressor and ventilatory responses to static contraction by an NK-1 receptor antagonist. 133 31

In homogenates of guinea pig lung, binding of 125I-Bolton-Hunter-labeled substance P (BHSP), Bolton-Hunter-labeled eledoisin (BHELE), and [125I]iodohistidyl neurokinin A (INKA) was investigated. Equilibrium dissociation constants (derived from "cold" saturation experiments) for BHSP, INKA, and BHELE were 0.96 +/- 0.15, 1.61 +/- 0.26, and 1.98 +/- 0.12 nM, respectively. Specific binding of all three radioligands was increased 2-3-fold by 10 microM phosphoramidon. The rank order of potency of unlabeled tachykinins in competing against BHSP was substance P (SP) greater than [Sar9,Met(O2)11]-SP greater than SP methyl ester greater than neuropeptide gamma greater than neurokinin A greater than or equal to neurokinin B = kassinin greater than or equal to eledoisin greater than or equal to scyliorhinin II much greater than neuropeptide K, indicating binding to sites with the general characteristics of NK1 receptors. Similar rank potency orders were observed for INKA and BHELE, showing binding to NK1 sites, rather than to NK2 or NK3 sites, which are labeled with high affinity by these radioligands in other tissues. For all radioligands, competition curves for SP and the NK1-selective agonist [Sar9,Met(O2)11]-SP could be resolved into two components, representing high and low affinity binding sites. These were present in the approximate ratios 2:3 (for BHSP), 1:1 (for INKA), and 8:1 (for BHELE). Other agonist competition curves also yielded high and low affinity components. The data suggest that BHSP and INKA bind partly and BHELE predominantly to high affinity NK1 receptors. The nature of the low affinity site(s) could be another tachykinin receptor or a low affinity state of the NK1 receptor. Binding to a "classical" NK2 receptor is unlikely, because selective NK2 receptor antagonists and analogs were very weak competitors. Our data suggest that, in addition to the NK1 receptor, another type of tachykinin receptor may exist in this tissue. The inability to detect NK2 binding sites is strikingly at variance with functional studies.
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PMID:Radioiodinated substance P, neurokinin A, and eledoisin bind predominantly in NK1 receptors in guinea pig lung. 137 Jul 5

Tachykinins, a family of biologically active related peptides, are found in variable amounts in the rat hypothalamus. We assessed the effects of five tachykinins, substance P (SP), neurokinin A (NKA), neuropeptide K (NPK), neuropeptide gamma (NP gamma), and neurokinin B (NKB), on LH release in different experimental model systems in ovariectomized rats. In the first series of experiments rats were ovariectomized and implanted with permanent cannulae in the third cerebroventricle of the rat brain. Two weeks later, the effects of intracerebroventricular injection of 0.5 or 1.25 nm various tachykinins on LH release were studied. The results showed that whereas SP, NKA, and NKB were ineffective, and NP gamma was marginally effective, NPK produced a long-lasting suppression of LH release. NPK decreased LH release in a dose- and time-related fashion. Similarly, in the second series of experiments, whereas SP and NKA were inactive, NPK completely suppressed the LH surge induced by progesterone in estrogen-primed ovariectomized rats. In the third series of experiments we observed that NK-2 receptor agonist [Nle10]NKA4-10, and not NK-1 receptor agonist [Sar9,Met(O2)11]SP, suppressed both the release of LH in vivo and basal and KCl-induced hypothalamic LHRH release in vitro. These results show that NPK is the most effective tachykinin in suppressing LH release, and the inhibitory response is mediated by hypothalamic NK-2 receptors. These findings are in accord with the hypothesis that NPK may serve as a hypothalamic inhibitory neurotransmitter/neuromodulator of LHRH secretion.
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PMID:Effects of tachykinins on luteinizing hormone release in female rats: potent inhibitory action of neuropeptide K. 137 55

We used radioligand binding to tissue homogenates and isometric contraction of muscle strips to characterize the substance P (SP) receptor on gastric smooth muscle from 1- (newborn) and 7-day-old and 4- and 11-wk-old (weanling) rabbits. Scatchard analysis for newborns was curvilinear, suggesting the presence of multiple binding sites. In newborns the dissociation constant (Kd) of high-affinity binding site was 2.2 +/- 0.3 nM, and the maximum binding (Bmax) was 0.57 +/- 0.06 pmol/mg DNA. The number of high-affinity binding sites decreased with age, disappearing by 11 wk. The Kd for the low-affinity site was more than two orders of magnitude greater than that of the high-affinity site. In competitive binding studies with [3H]SP, the order of potency for the neurokinins was SP much greater than neurokinin A (NKA) greater than neurokinin B (NKB), suggesting that the high-affinity binding sites were NK-1 receptors. [125I]NKA is also bound to newborn tissue homogenate with high affinity. With [125I]NKA the order was NKA greater than SP greater than NKB, suggesting that NK-2 receptors were also present. In contraction studies, atropine and tetrodotoxin had no effect on tachykinin-stimulated contraction, suggesting solely myogenic tachykinin effects on this tissue. In newborn rabbits, the potency and efficacy of SP and NKA were similar. The half-maximal effective dose (ED50) of SP was nearly two orders of magnitude less in newborn rabbits than in weanlings; the potency of NKA did not change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postnatal changes in the substance P receptor on rabbit gastric smooth muscle. 137 47

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

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