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)

Activation of any of the three known tachykinin receptors (NK1R, -2R, or -3R) can cause a rise in [Ca2+]i via a pertussis toxin-insensitive heterotrimeric G protein, Gq/G11, activation of phospholipase C (PLC), and a membrane depolarization. Tachykinins can depolarize neurons by two distinct mechanisms: 1) they reduce a resting K+ current in many neurons or 2) in parasympathetic and vagal primary sensory neurons, they activate a nonspecific cation current (Icat). Transient receptor potential channels (TRPC) are nonspecific cation channels that can be activated by a rise in [Ca2+]i in a PLC-dependent manner. The present work tests whether NK2R can signal TRPC. We applied standard whole cell patch-clamp recordings to HEK293 cells stably transfected with the human TRP3 channels (TRP3C), and transiently transfected with a functional NK2R-EGFP. Bath applied Substance P (SP, 1 microM) induced an Icat in the cells expressing both TRP3C and NK2R. Icat reached its peak value in approximately 3 min (195 +/- 120.0 s, mean +/- SE, n = 20), had a peak density of 11.3 +/- 3.48 pA/pF (n = 24), and was blocked by an NK2R-specific antagonist (SR48968, 100 nM). The Erev value for the SP current was 6.8 +/- 7.66 mV (n = 6), suggestive of a nonspecific cation channel. Icat was not measurable in TRP3C-expressing HEK293 cells without NK2R expression (n = 6) or in wild-type HEK293 cells with NK2R expression (n = 12). These data indicate that NK2R can be functionally coupled to TRP channels in HEK293 cells and suggest that SP-induced cation currents in vagal primary sensory neurons might be mediated by TRPC.
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PMID:Substance P evokes cation currents through TRP channels in HEK293 cells. 1296 82

A capillary liquid chromatographic column switching method has been developed for fast and sensitive determination of peptides in water samples. Sample volumes of 1 mL were loaded onto a (320 microm I.D. x30 mm) 10 microm Kromasil C(18) pre-column, providing on-line analyte enrichment, prior to back-flushed elution onto a (320 microm I.D. x150 mm) 3.5 microm Kromasil C(18) analytical column. Loading flow rates of 250 microL/min and a mobile phase composition of acetonitrile/water/trifluoroacetic acid (22/77.9/0.1, v/v) provided a total analysis time of less than 25 minutes for the test peptides angiotensin II, bombesin, bradykinin, corazonin, neurotensin and substance P, using temperature programmed elution. In addition, solvent gradient elution and combined solvent gradient elution and temperature programming were explored. Using on-capillary UV detection at 210 nm resulted in a concentration limit of detection (cLOD) of about 1 ng/mL. The method was validated over the concentration range 1-100 ng/mL, yielding a coefficient of correlation of 0.997 or better. The within-assay ( n=6) and between-assay ( n=6) precisions of peak areas were on average 6% RSD and 5% RSD, respectively. When the method was applied to spiked chlorinated tap water samples, it was found that peptides containing methionine, tryptophan and cystine were oxidized. Identification of the oxidation products of the peptides in hypochlorite-treated water was done with positive electrospray ionization time-of-flight mass spectrometric detection.
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PMID:Trace determination of peptides in water samples using packed capillary liquid chromatography with UV and MS detection and characterization of peptide oxidation products by MS. 1466 72

Neurokinin-1 receptor (NK1R)-expressing neurones that are involved in chemoreception at the retrotrapezoid nucleus (Nattie & Li, 2002b) are also prominent at locations that contain medullary serotonergic neurones, which are chemosensitive in vitro. In medullary regions containing both types, we evaluated their role in central chemoreception by specific cell killing. We injected (2 x 100 nl) (a) substance P-saporin (SP-SAP; 1 microm) to kill NK1R-expressing neurones, (b) a novel conjugate of a monoclonal antibody to the serotonin transporter (SERT) and saporin (anti-SERT-SAP; 1 microm) to kill serotonergic neurones, or (c) SP-SAP and anti-SERT-SAP together to kill both types. Controls received IgG-SAP injections (1 microm). There was no double-labelling of NK1R-immunoreactive (ir) and tryptophan-hydroxylase (TPOH)-ir neurones. Cell (somatic profile) counts showed that NK1R-ir neurones in the SP-SAP group were reduced by 31%; TPOH-ir neurones in the anti-SERT-SAP group by 28%; and NK1R-ir and TPOH-ir neurones, respectively, in the combined lesion group by 55% and 31% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). The treatments had no significant effect on sleep/wake time, body temperature, or oxygen consumption but all three reduced the ventilatory response to 7% inspired CO(2) in wakefulness and sleep by a similar amount. SP-SAP treatment decreased the averaged CO(2) responses (3, 7 and 14 days after lesions) in wakefulness and sleep by 21% and 16%, anti-SERT-SAP decreased the responses by 15% and 18%, and the combined treatment decreased the responses by 12% and 12% (P < 0.001; two-way ANOVA; P < 0.05, Tukey's post hoc test). We conclude that separate populations of serotonergic and adjacent NK1R-expressing neurones in the medulla are both involved in central chemoreception in vivo.
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PMID:Medullary serotonergic neurones and adjacent neurones that express neurokinin-1 receptors are both involved in chemoreception in vivo. 2666 Oct 54

Substance P (SP) has been characterized as an excitatory neurotransmitter and/or neuromodulator in the peripheral and central nervous systems. It is involved in mediating various biological functions such as smooth muscle contraction, neuronal excitation, and pain transmission. Although Lieb et al. reported that intravenous infusion of SP into healthy men led to an increase of paradoxical sleep latency and time awake, little is known about the function and target of SP on sleep-wakefulness cycle in the central nervous system. The ventrolateral preoptic area (vLPO) plays an important role in modulation of sleep-wakefulness cycle. The present study investigated the effect of SP on sleep-wakefulness cycle in the vLPO of rats. Slow wave sleep (SWS) was enhanced after SP was microinjected into bilateral vLPO, while SP receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)-benzyl ester, led to the opposite effect. The effect induced by SP was blocked by U73122, a phospholipase C inhibitor. In addition, 3-mercaptopropionic acid, a glutamic acid decarboxylase inhibitor that inhibits gamma-aminobutyric acid (GABA) synthesis and release, blocked the SP-induced sleep-promoting effect in the vLPO. These results indicate that SP has sleep-promoting effect in the vLPO possibly by GABAergic neurons.
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PMID:Substance P promotes sleep in the ventrolateral preoptic area of rats. 1552 48

Neurokinin 3 receptors (NK3-Rs) are expressed in the supraoptic nucleus (SON), and SON is innervated by substance P (SP)-expressing A1 neurons in the medulla. Because SP stimulates vasopressin (VP) and oxytocin release from explants of the hypothalamo-neurohypophyseal system (HNS), two hypotheses were tested: (1) SP-stimulated VP release is mediated by NK3-Rs, and (2) stimulation of the A1 pathway by hypotension activates SON NK3-Rs. Senktide, an NK3-R agonist, stimulated VP release from HNS explants, but neither a neurokinin 1 receptor antagonist [L732,138 (N-acetyl-L-tryptophan 3,5-bis(tri-fluoromethyl)benzyl ester)] nor two NK3-R antagonists (SB222200 and SB235375) prevented SP-stimulated VP release. Because the affinity of these antagonists for rat NK-Rs may limit their efficacy, NK3-R internalization was used to assess the ability of SP to activate SON NK3-Rs. Senktide, SP, or vehicle was microinjected above SON. The brain was perfused 5 min after injection and stained for NK3-R immunoreactivity. Using confocal microscopy, the number of NK3-R-immunoreactive (-IR) endosomes was counted in a 5.6(2) mu region of cytoplasm in SON neurons. Senktide, but not SP or vehicle, significantly increased the number of NK3-R-IR endosomes in the cytoplasm. When hypotension was induced with hydralazine, NK3-R internalization was observed within 5 min (p < 0.005). A decrease in cytoplasmic NK3-R immunoreactivity was observed within 15 min of hypotension. Unexpectedly, both senktide and hypotension resulted in translocation of NK3-R-IR immunoreactivity to the nucleus. Thus, although these studies do not identify SP as the NK3-R ligand, they do provide evidence for hypotension-induced release of an endogenous tachykinin in SON and evidence suggesting a role for NK3-Rs in transcription regulation.
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PMID:Role of neurokinin 3 receptors in supraoptic vasopressin and oxytocin neurons. 1553 80

The olfactory system plays important roles in various crustacean behaviors. Despite numerous studies on different aspects of the olfactory neural pathway, only the decapod-tachykinin-related peptide (decapod-TRP) has been identified as a neuromodulator in this processing to date. To establish the functions of other related neuropeptides, we initially performed cDNA cloning of FMRFamide-related peptide (FaRP) and allatostatin (AST)-like peptide from the crayfish Procambarus clarkii, followed by in situ hybridization (ISH) analysis of these peptides, along with decapod-TRP, orcokinin, and crustacean-SIFamide. Cloned FaRP cDNA encodes seven copies of C-terminal RN(F/Y)LRFamide-containing peptide, whereas AST-like peptide cDNA comprises 29 copies of AST-like peptide (-YXFGLamide) and three additional putative peptides. ISH analysis of the brain revealed specific expression of crustacean-SIFamide mRNA in most projection neurons (cell cluster 10), and predominant localization of other mRNAs to interneurons. The data suggest that the crustacean-SIFamide neuropeptide is involved in output of the deutocerebrum to the protocerebrum. Double-fluorescence ISH data further disclose that, in cluster 9, orcokinin is coexpressed in decapod-TRP-specific interneurons, whereas AST-like peptide-containing cells do not overlap with orcokinin-expressing cells. On the other hand, FaRP-expressing cells overlap with both orcokinin- and AST-like peptide-specific cells. In cluster 11, where signals for AST-like peptide are absent, a number of interneurons express both decapod-TRP and orcokinin, emphasizing a close relationship between these two factors with regard to olfactory processing, and possibly tactile and/or visual sensory systems. These characteristic expression patterns of neuropeptides support their distinct involvement in the modulation of olfactory processing.
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PMID:Characteristic expression patterns of allatostatin-like peptide, FMRFamide-related peptide, orcokinin, tachykinin-related peptide, and SIFamide in the olfactory system of crayfish Procambarus clarkii. 1652 23

Ghrelin increases electrically evoked, neuronally mediated contractions of rat isolated forestomach, a prokinetic-like activity. Since the nerve type sensitive to ghrelin is unclear, we examined the activity of ghrelin in the presence of antagonists at receptors for the main gastric motor neurotransmitters. Electrical field stimulation (EFS; 5 Hz, 0.5 ms, +/-50 V, 30 s every 3 min) of circular muscle preparations evoked tetrodotoxin 1 microM-sensitive responses, consisting of a small initial contraction followed by a further contraction or more usually, by muscle relaxation. Termination of EFS evoked a large rapidly developing after-contraction. Atropine 1 microM prevented contractions during EFS, increased any relaxations and prolonged the after-contractions. Nomega-Nitro-L-arginine-methyl-ester-hydrochloride (L-NAME) 0.3 mM prevented relaxations during EFS, changing the triphasic response into a monophasic contraction. The tachykinin NK1 and tachykinin NK2 receptor antagonists N-acetyl-L-tryptophan-3,5-bistrifluoromethyl-benzyl-ester (L-732,138 1 microM) and Cyclo[Gln-Trp-Phe-Gly-Leu-CH2N(CH3)-Leu] (MDL-29,913 1 microM) each reduced EFS-evoked relaxations; the latter also reduced the after-contractions. The tachykinin NK3 receptor antagonist (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB-235375, 0.1 microM) had no effects. The combination of tachykinin NK(1,2,3) receptor antagonists reduced the after-contractions and abolished relaxations during EFS, replacing this with a contraction. In control tissues, ghrelin 1 microM increased EFS-induced contractions and tended to reduce any relaxations. In the presence of atropine 1 microM, L-NAME 0.3 mM or the tachykinin receptor antagonists (as above), ghrelin 1 microM increased any EFS-induced contraction but in the presence of atropine had no effects on EFS-evoked relaxations. We conclude that EFS evokes responses mediated by acetylcholine, nitric oxide and tachykinins. Ghrelin facilitates both cholinergic and tachykininergic excitatory pathways, consistent with activity within the enteric nervous system and possibly the vagus nerve.
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PMID:The prokinetic-like activity of ghrelin in rat isolated stomach is mediated via cholinergic and tachykininergic motor neurones. 1685 71

Neurogenic inflammatory responses have recently been linked to both acute and chronic pathological conditions in the urinary tract. Neurogenic inflammation encompasses a series of vascular and non-vascular inflammatory responses, triggered by the activation of primary sensory neurons and the subsequent release of inflammatory neuropeptides, including substance P and calcitonin gene-related peptide. The reduction of neurogenic inflammatory responses may be key in the mode of action of the adrenergic alpha(1)-adrenoceptor antagonists used to treat lower urinary tract symptoms (LUTS). Indeed, the alpha(1)-adrenoceptor antagonist alfuzosin inhibits expression of the oncogene c-fos- a marker of nociceptive pathway activation - evoked by cyclophosphamide in rats. Capsaicin ameliorates urinary bladder symptoms through its stimulatory action on the transient receptor potential vanilloid 1 (TRPV1) calcium channel, resulting in desensitization of bladder sensory nerve terminals. Involvement of the TRP cation channel, subfamily A, member 1 (TRPA1) has also been reported in models of neurogenic inflammation and nociception promoted by the cyclophosphamide metabolite, acrolein. Blockade by alfuzosin demonstrates the beneficial effects of alpha(1)-adrenoceptor antagonists on neurogenic inflammation via the transient receptor potential family of ionic channels. Consequently, these drugs may have an important role in reducing LUTS.
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PMID:The concept of neurogenic inflammation. 1830 78

Substance P (SP) is upregulated in HIV infection in adult men and women, as determined by increased plasma levels. There is a reciprocal and bidirectional relationship between substance P and HIV in HIV-infected monocyte-derived macrophages and cell lines (e.g., THP-1). Substance P up-regulates HIV and HIV up-regulates SP protein expression. Neurokinin-1 receptor (NK1R) antagonists inhibit HIV infectivity through downregulation of the chemokine receptor, CCR5, and downregulation of HIV LTR. Neurokinin-1 receptor is expressed in full-length and truncated forms. The full-length NK1R is capable of signaling, whereas the truncated NK1R primes the chemokine receptor CCR5. Both full-length and truncated NK1R are expressed in several brain regions in human autopsy brains. SP-NK1R interactions have regulatory roles in inflammation and infection. The differential expression of truncated and full-length NK1R has important biological consequences. These include receptor-receptor interaction (e.g., NK1R-CCR5); changes in expression during cell differentiation (e.g., THP-1 cells); and differences in regional tissue distribution (e.g., differences in different brain regions). NK1R-SP receptor pathways are important cell regulatory pathways.
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PMID:Neurokinin-1 receptor expression and function in human macrophages and brain: perspective on the role in HIV neuropathogenesis. 1907 68

Manipulation of neurotrophin (NT) signalling by administration or depletion of NTs, by transgenic overexpression or by deletion of genes coding for NTs and their receptors has demonstrated the importance of NT signalling for the survival and differentiation of neurons in sympathetic and dorsal root ganglia (DRG). Combination with mutation of the proapoptotic Bax gene allows the separation of survival and differentiation effects. These studies together with cell culture analysis suggest that NT signalling directly regulates the differentiation of neuron subpopulations and their integration into neural networks. The high-affinity NT receptors trkA, trkB and trkC are restricted to subpopulations of mature neurons, whereas their expression at early developmental stages largely overlaps. trkC is expressed throughout sympathetic ganglia and DRG early after ganglion formation but becomes restricted to small neuron subpopulations during embryogenesis when trkA is turned on. The temporal relationship between trkA and trkC expression is conserved between sympathetic ganglia and DRG. In DRG, NGF signalling is required not only for survival, but also for the differentiation of nociceptors. Expression of neuropeptides calcitonin gene-related peptide and substance P, which specify peptidergic nociceptors, depends on nerve growth factor (NGF) signalling. ret expression indicative of non-peptidergic nociceptors is also promoted by the NGF-signalling pathway. Regulation of TRP channels by NGF signalling might specify the temperature sensitivity of afferent neurons embryonically. The manipulation of NGF levels "tunes" heat sensitivity in nociceptors at postnatal and adult stages. Brain-derived neurotrophic factor signalling is required for subpopulations of DRG neurons that are not fully characterized; it affects mechanical sensitivity in slowly adapting, low-threshold mechanoreceptors and might involve the regulation of DEG/ENaC ion channels. NT3 signalling is required for the generation and survival of various DRG neuron classes, in particular proprioceptors. Its importance for peripheral projections and central connectivity of proprioceptors demonstrates the significance of NT signalling for integrating responsive neurons in neural networks. The molecular targets of NT3 signalling in proprioceptor differentiation remain to be characterized. In sympathetic ganglia, NGF signalling regulates dendritic development and axonal projections. Its role in the specification of other neuronal properties is less well analysed. In vitro analysis suggests the involvement of NT signalling in the choice between the noradrenergic and cholinergic transmitter phenotype, in the expression of various classes of ion channels and for target connectivity. In vivo analysis is required to show the degree to which NT signalling regulates these sympathetic neuron properties in developing embryos and postnatally.
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PMID:Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. 1938 88


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