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)

In view of the widespread use of non-steroidal anti-inflammatory drugs for treatment of inflammatory pain, we determined the effects of the non-steroidal anti-inflammatory drug, indomethacin, on dorsal horn neurons in the rat spinal cord in vivo. At 2.0-12.0 mg/kg (i.v.), indomethacin depressed the responses of spinal dorsal horn neurons to the effects of iontophoretic application of substance P, N-methyl-D-aspartate, quisqualate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. As indomethacin inhibits cyclo-oxygenase, these are the first data linking prostanoids and possibly arachidonic acid and other eicosanoids to the effects of substance P and glutamate in the spinal dorsal horn. As responses to iontophoretic application can be assumed to have been postsynaptic and as indomethacin had an effect generalized to all excitatory responses, we suggest a postsynaptic site for cyclo-oxygenase. We also suggest that elements in the cyclo-oxygenase signal transduction pathway may thus mediate at least some of the effects of substance P and glutamate receptor activation. Activation of the cyclo-oxygenase pathway in CNS neurons is Ca2- dependent, and activation of both N-methyl-D-aspartate and substance P receptors increases intracellular Ca2+. This led to the expectation that indomethacin would have a greater effect on responses to N-methyl-D-aspartate than to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, but the reverse was observed. Thus, in addition to a mediator role, we hypothesize that an element(s) of the cyclo-oxygenase pathway may regulate the efficacy of excitation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors and perhaps other membrane-bound receptors. The cyclo-oxygenase signal transduction pathway thus appears to play at least two major roles in regulation of sensory processing in the spinal cord. Therefore, non-steroidal anti-inflammatory drugs, via cyclo-oxygenase inhibition, may have multiple actions in control of spinal sensory mechanisms.
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PMID:Mediation and modulation by eicosanoids of responses of spinal dorsal horn neurons to glutamate and substance P receptor agonists: results with indomethacin in the rat in vivo. 1047 75

The aim of this study was to examine whether anorexia nervosa and bulimia nervosa are accompanied by lower serum activity of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5), a membrane-bound serine protease that catalyses the cleavage of dipeptides from the amino-terminus of oligo- and polypeptides. Substrates of DPP IV are, amongst others, neuroactive eptides, such as substance P, growth hormone releasing hormone, neuropeptide Y, and peptide YY. DPP IV activity was measured in the serum of 21 women with anorexia nervosa, 21 women with bulimia nervosa and 18 normal women. Serum DPP IV activity was significantly lower in patients with anorexia nervosa and bulimia nervosa than in the normal controls. In the total study group, there were significant and inverse relationships between serum DPP IV activity and the total scores on the Bulimic Investigatory Test, Edinburgh, the Eating Disorder Inventory (EDI) and the Hamilton Depression Rating Scale. In the total study group no significant correlations between DPP IV and age, body weight or body mass index could be found. It is concluded that lowered serum DPP IV activity takes part in the pathophysiology of anorexia and bulimia nervosa. It is hypothesised that a combined dysregulation of DPP IV and neuroactive peptides, which are substrates of DPP IV, e.g. neuropeptide Y and peptide YY, could be an integral component of eating disorders.
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PMID:Lowered serum dipeptidyl peptidase IV activity in patients with anorexia and bulimia nervosa. 1085 24

Various hypotheses have been proposed to account for the mechanical hyperalgesia and spontaneous pain seen in animal models of peripheral neuropathy. The purpose of the present study was to determine whether there exists a spinal neuronal correlate to these properties. An experimental neuropathy was induced in male Sprague-Dawley rats by placing a 2-mm PE-90 polyethylene cuff around the sciatic nerve. All rats were subsequently confirmed to exhibit mechanical allodynia in the von Frey test. After induction of anaesthesia with pentobarbital and acute spinalization at T9, electrophysiological experiments were performed, recording extracellular single unit activity from ipsi- and contralateral wide dynamic range dorsal horn neurons in spinal segments L1-4. On-going activity was greater in short-term (11-22 days after cuff implantation) and long-term (42-52 days) cuff-implanted rats; 38 spikes/s in short-term versus 19 spikes/s in controls; 29 spikes/s in long-term ipsi- and contralateral neurons. Receptive fields in controls were always restricted, but in almost all cuff-implanted rats extended over the whole hind paw. Responses to noxious mechanical (pinch) and noxious heat stimulation of the cutaneous receptive field in controls consisted of the typical fast initial discharge followed by an afterdischarge. In all neurons from cuff-implanted rats the initial discharge resembled that in controls. However, the afterdischarge, particularly that in response to noxious pinch, was markedly greater in both magnitude and duration. It is suggested that the greater on-going discharge is the cellular correlate of spontaneous pain, and the potentiation of the afterdischarge in response to noxious stimulation is the correlate of hyperalgesia. Given that acutely spinalized rats were tested, only peripheral and/or spinal mechanisms can be considered to explain these data. Considering all the data, it can be concluded that there is a greater change in fibres mediating noxious mechanical than noxious thermal inputs. Among different hypotheses, the one with which the present data are most compatible is that which proposes that chronic nerve injury or inflammation induces phenotypic changes predominantly in myelinated afferents. There may be a redistribution of membrane-bound ion channels, predominantly sodium channels, which leads to ectopic activity and thus spontaneous discharge of dorsal horn neurons. With regard to mechanical stimulation-evoked synaptic input, the central terminals of myelinated afferents expand into regions of the spinal cord which normally receive their predominant input from unmyelinated nociceptive afferents. This may be coupled with a change in these myelinated afferents so that they now synthesize and release peptides, primarily substance P, from their central terminals with the result that the effects of their chemical mediators of synaptic transmission add to the effects of nociceptive inputs leading to exaggerated responses to painful stimuli, thus the basis of clinical hyperalgesia.
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PMID:Cellular mechanisms of hyperalgesia and spontaneous pain in a spinalized rat model of peripheral neuropathy: changes in myelinated afferent inputs implicated. 1088 40

The mammalian bradykinin-degrading enzyme aminopeptidase P (AP-P; E. C. 3.4.11.9) is a metal-dependent enzyme and is a member of the peptidase clan MG. AP-P exists as membrane-bound and cytosolic forms, which represent distinct gene products. A partially truncated clone encoding the cytosolic form was obtained from a human pancreatic cDNA library and the 5' region containing the initiating Met was obtained by 5' rapid accumulation of cDNA ends (RACE). The open reading frame encodes a protein of 623 amino acids with a calculated molecular mass of 69,886 Da. The full-length cDNA with a C-terminal hexahistidine tag was expressed in Escherichia coli and COS-1 cells and migrated on SDS-PAGE with a molecular mass of 71 kDa. The expressed cytosolic AP-P hydrolyzed the X-Pro bond of bradykinin and substance P but did not hydrolyze Gly-Pro-hydroxyPro. Hydrolysis of bradykinin was inhibited by 1,10-phenanthroline and by the specific inhibitor of the membrane-bound form of mammalian AP-P, apstatin. Inductively coupled plasma atomic emission spectroscopy of AP-P expressed in E. coli revealed the presence of 1 mol of manganese/mol of protein and insignificant amounts of cobalt, iron, and zinc. The enzymatic activity of AP-P was promoted in the presence of Mn(II), and this activation was increased further by the addition of glutathione. The only other metal ion to cause slight activation of the enzyme was Co(II), with Ca(II), Cu(II), Mg(II), Ni(II), and Zn(II) all being inhibitory. Removal of the metal ion from the protein was achieved by treatment with 1,10-phenanthroline. The metal-free enzyme was reactivated by the addition of Mn(II) and, partially, by Fe(II). Neither Co(II) nor Zn(II) reactivated the metal-free enzyme. On the basis of these data we propose that human cytosolic AP-P is a single metal ion-dependent enzyme and that manganese is most likely the metal ion used in vivo.
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PMID:Cloning, expression, and characterization of human cytosolic aminopeptidase P: a single manganese(II)-dependent enzyme. 1110 90

Antioxidants and antioxidant enzymes are known to protect against cell death induced by reactive oxygen species. However, apart from directly quenching free radicals, little is known about the effect of antioxidants on hormone-activated second messenger systems. We previously found that antioxidants such as 17-beta estradiol and resveratrol activate membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF), in PC12 cells. It is possible that other antioxidants may also activate membrane-bound guanylate cyclase GC-A. The aim of this study was to determine if dithiothreitol (DTT), vitamin C, and vitamin E activate membrane-bound guanylate cyclase GC-A in PC12 cells. The results showed that both DTT and vitamin C increased cGMP levels in PC12 cells, whereas vitamin E had no effect. DTT and vitamin C inhibited membrane-bound guanylate cyclase activity stimulated by ANF in PC12 cells. In contrast, DTT and vitamin C had no effect on soluble guanylate cyclase activity stimulated by substance P. Furthermore, NO synthase inhibitors L-NAME and aminoguanidine did not affect DTT- and vitamin C-stimulated guanylate cyclase activity. The results indicate that DTT and vitamin C, but not vitamin E, activate membrane-bound guanylate cyclase GC-A in PC12 cells.
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PMID:Antioxidants, vitamin C and dithiothreitol, activate membrane-bound guanylate cyclase in PC12 cells. 1127 22

G protein-coupled receptor kinases (GRKs) phosphorylate agonist-occupied G protein-coupled receptors, leading to receptor desensitization. Seven GRKs, designated GRK1 through 7, have been characterized. GRK5 is negatively regulated by protein kinase C. We investigated whether human substance P receptor (hSPR) is a substrate of GRK5. We report that membrane-bound hSPR is phosphorylated by purified GRK5, and that both the rate and extent of phosphorylation increase dramatically in the presence of substance P. The phosphorylation has a high stoichiometry (20+/-4 mol phosphate/mol hSPR) and a low K(m) (1.7+/-0.1 nM). These data provide the first evidence that hSPR is a substrate of GRK5.
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PMID:Human substance P receptor undergoes agonist-dependent phosphorylation by G protein-coupled receptor kinase 5 in vitro. 1206 42

Neprilysin (NEP) is an endopeptidase, which has an important role in the inactivation of mammalian tachykinins. NEP-like activity has also been found in the brain of several insects; however, the lack of information about the cellular localization of this peptidase has hindered our understanding of its role in peptidergic signaling in insects. We now provide evidence that membrane-bound NEP is involved in the inactivation of tachykinin-related peptides in the brain of the cockroach, Leucophaea maderae, and the locust, Locusta migratoria. The L. maderae enzyme cleaved the cockroach peptide LemTRP-1 and the mammalian NEP substrate [DAla(2),Leu(5)]enkephalin at the Gly-Phe peptide bond. The enzyme was acted upon by the NEP inhibitors phosphoramidon (IC(50), 0.64 microM) and thiorphan (IC(50), 1.23 microM), and the detergent-solubilized enzyme had an Mr of approximately 300,000 and a neutral pH optimum. This endopeptidase cleaved another insect tachykinin-related peptide, CavTK-II, in a predictable manner at the Ala-Phe peptide bond, suggesting that the peptidase can hydrolyse tachykinin-related peptides with different structures. NEP activity was histochemically localized in several, but not all, regions of neuropil in the brain of L. maderae, including the central body, the lobula of the optic lobe, and the tritocerebrum. All of these regions are known to receive neuronal processes containing tachykinin-related peptides. A slightly different distribution pattern for NEP was observed in the brain of L. migratoria. Again, NEP was localized to regions of the neuropil that also display tachykinin-related peptide immunoreactivity. The data reported provide evidence for an evolutionary conserved role for NEP in the inactivation of tachykinin-related peptides in the brain.
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PMID:Identification and localization of a neprilysin-like activity that degrades tachykinin-related peptides in the brain of the cockroach, Leucophaea maderae, and locust, Locusta migratoria. 1254 24

This review summarizes some basic properties and distribution of angiotensin I converting enzyme (ACE). ACE is one of several biologically important ectoproteins that exists in both membrane-bound and soluble forms. Localized on the surface of various cells, ACE is inserted at the cell membrane via its carboxyl terminus. Human plasma ACE originates from endothelial cells while other body fluids may contain ACE that originates from epithelial, endothelial or germinal cells. The two isoforms of ACE, the two-domain somatic form and the single domain germinal form, convert angiotensin I to angiotensin II, and metabolize kinins and many other biologically active peptides, including substance P, chemotactic peptide and opioid peptides. The broad spectrum of substrates for ACE and its wide distribution throughout the body indicates that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in additional physiologic processes such as neovascularization, fertilization, atherosclerosis, kidney and lung fibrosis, myocardial hypertrophy, inflammation and wound healing. Future research should explore the possible functions of tissue ACE and its systemic role as a pressor agent. ACE inhibitors have achieved widespread use in the treatment of hypertension and the protection of end-organ damage in cardiovascular and renal diseases. Potential problems related to side effects and compliance of such therapy need to be addressed. A safer way of producing therapeutic effects is promised by the delivery of the ACE antisense sequences by a vector producing a permanent inhibition of ACE and long-term control of blood pressure in hypertensive patients.
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PMID:Properties and distribution of angiotensin I converting enzyme. 1257 Jul 87

Metalloendopeptidases of the M13 family were shown to play critical roles in normal physiological processes such as pain control, hypertension and phosphate metabolism, and in pathological states such as Alzheimer's disease. Recently, NL1, a novel member of the family, has been identified and shown to be expressed in several tissues both as a membrane-bound and a secreted protein. As a further step to understand the physiological role(s) of NL1 in mouse, we mapped NL1 mRNA expression pattern in embryos and in young animals at postnatal days p1 and p3, and in adult nervous tissue, using in situ hybridization at the cellular level. No expression could be detected in embryos and young animals. In contrast, NL1 expression was evident in adult brain, pituitary gland and spinal cord. In the central nervous system (CNS), NL1 mRNA was predominantly found in the ventro-posterior regions, which are mostly associated with vegetative functions. At the cellular level, NL1 mRNA was non-uniformly distributed within subpopulations of neurons. In the spinal cord, specific signal was observed in the gray matter. Then, in order to identify putative relevant substrates for NL1, we studied its enzymatic activity towards peptides known to be co-expressed in the NL1-positive domains. Our study showed that NL1 degrades several of these peptides in vitro, the most readily degraded peptides being Bradykinin and Substance P. These results suggest that NL1 is likely to play a critical role in the central nervous system.
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PMID:The neuropeptide-degrading enzyme NL1 is expressed in specific neurons of mouse brain. 1449 88

Neurokinin-1 receptor (NK-1R), a high-affinity plasma membrane-bound receptor for neurokinin substance P, plays important roles in the onset of the pathophysiological responses. To test whether the transcript levels of gene encoding NK-1R in organs are affected by sidestream cigarette smoke (SSCS) exposure, the C57BL/6 mice were randomly assigned to five groups (six/group) in a study of the dose-effect relationship. The mice were exposed to 0 (filtered room air), 2, 4, 8 and 16 mg total particulate matter (TPM) of SSCS/exposure/day, respectively, for seven days through a nose-only exposure chamber (IN-TOX, Albuquerque, NM, USA). The levels of NK-1R mRNA in the lung, heart, liver, kidney and spleen tissues were detected by reverse transcription-polymerase chain reaction (RT-PCR) techniques and normalized against GAPDH expression. NK-1R mRNA in heart tissue showed SSCS-induced dose-dependent downregulation, with minimum expression at a dose of 8.0 mg TPM. Whereas, the levels of NK-1R mRNA in the liver were upregulated to 2.86 and 5.13-fold after exposure to 2.0 and 4.0 mg TPM of SSCS respectively, then returned to 4.19 and 3.93-fold at the exposure doses of 8.0 and 16.0 mg TPM, respectively, when compared to that of the control. In the kidney, SSCS exposure at a dose of 2.0 TPM, but not higher than that level, induced significant elevation of NK-1R mRNA expression. These findings suggest that there are the paracrine and/or autocrine signalling mechanisms through receptor-ligand interactions. No alteration of NK-1R gene expression was observed in the lungs and spleen tissues in this study. The tissue-specific patterns by which SSCS affect NK-1R gene expression in these organs may partially explain dissimilarity of NK-1R activation and the associated toxicity caused by environmental tobacco smoke.
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PMID:Tissue-specific patterns of neurokinin-1 receptor (NK-1R) gene expression in mice exposed to sidestream cigarette smoke. 1522 33

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