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)

To identify the tachykinin receptor subclass involved in the central cardiovascular and behavioral actions of substance P (SP), we compared the central actions of SP with those of neurokinin A (NKA) and senktide in conscious chronically instrumented rats. Intracerebroventricular (i.c.v.) injection of SP (an NK1 agonist) and NKA (an NK2 agonist) increased mean arterial pressure (MAP) and heart rate (HR) dose dependently and these cardiovascular responses were associated with the behavioral responses, comprising excessive grooming and exploring. Both peptides were equipotent to produce the cardiovascular and the behavioral responses. Senktide (a highly selective NK-3 agonist), injected i.c.v. increased the HR markedly. The behavioral response, 'wet dog shakes', was observed most frequently after senktide and was dissociated from the HR response. Pretreatment with a peripheral NK-1-selective antagonist, L-668,169, attenuated the NKA-induced cardiovascular and behavioral responses but not the SP-induced responses. However, pretreatment with a peripheral NK-2-selective antagonists, L-659,877, attenuated the SP-induced responses but not the NKA-induced responses. These results suggest that the central cardiovascular and behavioral actions of SP and NKA are mediated by different subclasses of receptors and that the receptor subclasses which are specific for the central nervous system differ from those which mediate the peripheral actions of the two tachykinins.
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PMID:Identification of the central tachykinin receptor subclass involved in substance P-induced cardiovascular and behavioral responses in conscious rats. 138 76

1. The effect of systemic administration of ruthenium red on bronchospasm induced by acetylcholine, capsaicin or selective tachykinin receptor agonists ([Sar9]SP sulfone or [beta Ala8]-neurokinin A (NKA)-(4-10) for NK-1 and NK-2 receptors, respectively) was studied in anaesthetized guinea-pigs. 2. The bronchospasm induced by capsaicin was reduced by ruthenium red, which did not affect the response induced by acetylcholine. Atropine, which totally blocked the response to acetylcholine, also partially blocked the bronchospasm induced by capsaicin. 3. The inhibitory action of atropine and ruthenium red on the bronchospasm produced by capsaicin was additive, independently from the order of administration of the two antagonists. 4. Ruthenium red induced an increase in [Sar9]SP sulfone-bronchospasm and a marked enhancement of the bronchomotor response to [beta Ala8]NKA-(4-10). This latter was antagonized by the prior administration of the selective NK-2 receptor antagonist MEN 10,376. 5. Pretreatment with guanethidine or propranolol increased the airway constriction induced by [beta Ala8]NKA-(4-10). Furthermore, pretreatment with guanethidine prevented the enhancement induced by ruthenium red, showing that activation of NK-2 receptors influences the sympathetic bronchodilator drive to the airways. 6. It is concluded that ruthenium red antagonizes selectively the in vivo excitatory effect of capsaicin in guinea-pig airways. Furthermore, the additivity of the blocking action of ruthenium red and atropine indicates that two distinct mechanisms take place in bronchospastic response to i.v. capsaicin in this species.
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PMID:Effect of ruthenium red on the bronchoconstriction induced by capsaicin and by selective tachykinin receptor agonists in anaesthetized guinea-pig. 138 38

Stimulation of sensory nerves in the airway mucosa of the rat evokes the release of inflammatory peptides such as substance P, which can increase microvascular permeability, resulting in a phenomenon known as neurogenic plasma extravasation. The change in vascular permeability is mediated by NK-1 receptors and is caused by the formation of gaps between endothelial cells of postcapillary venules and small collecting venules, which are the same vessels as are affected by inflammatory mediators such as histamine and bradykinin. Respiratory tract infections caused by Sendai virus or Mycoplasma pulmonis can intensify neurogenic plasma extravasation in the airway mucosa, as indicated by the amount of microvascular leakage evoked by substance P or capsaicin. M. pulmonis infections can produce a 30-fold increase in the magnitude of neurogenic plasma extravasation, which is evident 4 wk after infection and may be permanent. A proliferation of venules in the airway mucosa and heightened sensitivity of these vessels to inflammatory mediators are key elements of the increase in plasma extravasation. Exposure of M. pulmonis-infected rats to ammonia exacerbates the infections and further augments the responsiveness of mucosal venules to inflammatory mediators. Despite this increased responsiveness, the vessels are not abnormally leaky in the absence of inflammatory stimuli. These findings emphasize the importance of airway infections as factors that can cause a potent, long-lasting increase in the sensitivity of the microvasculature of the airway mucosa to inflammatory mediators.
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PMID:Infections intensify neurogenic plasma extravasation in the airway mucosa. 144 6

NKA (4-10), the C-terminal heptapeptide fragment (Asp-Ser-Phe-Val-Gly-Leu-Met-NH2) of tachykinin NKA, is more active than the parent native compound in the interaction with the NK-2 receptor. Substitution of Gly8 with the more flexible residue beta-Ala8 increases its selectivity with respect to other two known receptors (NK-1 and NK-3), whereas substitution with either D-Ala8 or GABA8 deprives the peptide of its biological activity. These findings can be interpreted by a conformational analysis based on NMR studies in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture combined with internal energy calculations. NKA(4-10) is characterized by a structure containing a type I beta-turn extending from Ser5 to Gly8, followed by a gamma-turn centered on Gly8, whereas for [beta-Ala8]NKA(4-10) is possible to suggest a type I beta-turn extending from Ser5 to beta-Ala8, followed by a C8 turn comprising beta-Ala8 and Leu9 and by another beta-turn extending from beta-Ala8 to the terminal NH2. The preferred conformation of [beta-Ala8]NKA(4-10) is not compatible with models for NK-1 and NK-3 agonists proposed on the basis of rigid peptide agonists [Levian-Teitelbaum et al. (1989) Biopolymers 28, 51-64; Sumner & Ferretti (1989) FEBS Lett. 253, 117-120]. The preferred solution conformation of [beta-Ala8]NKA(4-10) may thus be considered as a likely bioactive conformation for NK-2 selective peptides.
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PMID:Conformation-activity relationship of tachykinin neurokinin A (4-10) and of some [Xaa8] analogues. 165 41

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

The tachykinins, substance P, neurokinin A and neurokinin B, belong to a structural family of peptides. In mammalian airways, substance P and neurokinin A are colocalized to afferent C-fibres. Substance P-containing fibres are close to bronchial epithelium, smooth muscle, mucus glands and blood vessels. Sensory neuropeptides may be released locally, possibly as a result of a local reflex, and produce bronchial obstruction through activation of specific receptors on these various tissues. Three types of tachykinin receptors, namely NK-1, NK-2 and NK-3 receptors, have been characterized by preferential activation by substance P, neurokinin A and neurokinin B respectively. NK-1 and NK-2 receptors were recently cloned. The determination of receptor types involved in the effects of tachykinins in the airways has been done with synthetic agonists and antagonists binding specifically to NK-1, NK-2 and NK-3 receptors. Although the existence of species differences, the conclusion that bronchial smooth muscle contraction is mainly related to activation of NK-2 receptors on bronchial smooth muscle cell has been drawn. The hypothesis of a NK-2 receptor subclassification has been proposed with NK-2A receptor subtype in the guinea-pig airways. Other effects in the airways are related to stimulation of NK-1 receptors on mucus cells, vessels, epithelium and inflammatory cells. A non-receptor-mediated mechanism is also involved in the effect of substance P on inflammatory cells and mast cells.
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PMID:Tachykinin receptors and the airways. 166 Sep 52

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 selective NK-1, NK-2 and NK-3 tachykinin agonists in midbrain dopamine cell containing regions were investigated in the rat. The NK-3 agonist senktide induced locomotion, rearing and sniffing following infusion into the substantia nigra pars compacta, and to a lesser extent in the ventral tegmental area. These behavioural responses were not seen following infusion of the selective NK-1 agonist [Sar9,Met (O2)11]SP or the NK-2 agonist [N1e10]NKA4-10. In contrast, grooming was induced only by the NK-1 agonist administered into the substantia nigra. Yawning, chewing mouth movements and wet dog shakes were all seen following infusion of senktide into the ventral tegmental area. These findings suggest that (i) dopamine-mediated behavioural responses seen following tachykinin administration into the midbrain are dependent upon stimulation of NK-3 tachykinin receptors, (ii) tachykinin-induced grooming is mediated by stimulation of NK-1 receptors and (iii) some of the previously described 5-HT mediated behaviours seen following administration of NK-3 tachykinin agonists are probably generated by stimulation of 5-HT cell bodies in the ventral tegmental area.
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PMID:Behavioural effects of selective tachykinin agonists in midbrain dopamine regions. 166 12

1. The NK-1 selective agonists [beta-Ala4, Sar9]SP-(4-11) sulphone and [pGlu6, Pro9]SP-(6-11) dose-dependently increased vascular permeability in various segments of rat and guinea-pig tracheo-bronchial region, while the NK-2 ([Nle10]NKA-(4-10) and [beta-Ala8]NKA-(4-10)) or NK-3 ([MePhe7]NKB and [MePhe7]NKB-(4-10)) selective agonists were inactive. These findings provide evidence that the inflammatory response of the airway to intravenous tachykinins is exclusively mediated by the NK-1 receptor subtype. 2. Plasma protein extravasation induced by capsaicin was more intense in the caudal segments of the rat airways and paralleled the tissue concentration of substance P-like and calcitonin gene-related peptide-like immunoreactivity. The response to capsaicin was greatly reduced in rats pretreated with high dose of the toxin (655 mumol kg-1 s.c., 3 weeks before) and was smallest in the airway regions where the depletion of neuropeptides had been more severe. 3. The depletion of transmitters from capsaicin-sensitive nerves did not affect the inflammatory response of the airway to serotonin (500 nmol kg-1 i.v.), while increased responsiveness to a threshold dose (0.37 nmol kg-1 i.v.) of [beta-Ala4, Sar9]SP-(4-11) sulphone was observed. This finding gives preliminary evidence that, after depletion of transmitters from capsaicin-sensitive nerves, upregulation of NK-1 receptors may develop in rat trachea.
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PMID:Effect of synthetic tachykinin analogues on airway microvascular leakage in rats and guinea-pigs: evidence for the involvement of NK-1 receptors. 168 26

Neurokinins regulate gastrointestinal motility by interacting with receptors on both muscle layers and on myenteric plexus neurons. To determine if specific neurokinin (NK) receptor agonists can mediate inhibitory effects on myenteric neurons, we studied the effect of the NK-1 agonist substance P methylester (SPME) and the putative endogenous NK-2 receptor ligand neurokinin A (NKA) on [3H]acetylcholine [( 3H]ACh) release induced by electrical field stimulation from muscle strips cut from the canine gastric antrum. SPME but not NKA caused a dose-dependent inhibition of stimulated [3H]ACh release in tissues containing the myenteric plexus. The inhibition was not seen in longitudinal muscle without myenteric plexus. Pretreatment of tissues with indomethacin or antiserum to vasoactive intestinal polypeptide (VIP) but not naloxone or adrenergic or cholingergic blockade abolished the SPME-induced inhibition. Exogenous VIP stimulated the release of prostaglandin E2 (PGE2) from full thickness strips, and both VIP and PGE2 inhibited [3H]ACh release induced by electrical depolarization. These findings suggest that NK-1 receptor agonists can selectively inhibit stimulated [3H]ACh release and that this inhibition may involve the release of VIP and PGE2 from neurons within the myenteric plexus.
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PMID:Neurokinin inhibition of cholinergic myenteric neurons in canine antrum. 168 19


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