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)

Neuropeptides in dorsal root ganglia (DRG) have been implicated in the pathogenesis of pain and neurogenic inflammation in experimental and clinical arthritis. Recently we demonstrated increased levels of substance P (SP) and calcitonin gene-related peptide (CGRP) confined to innervating DRG in adjuvant-mediated monoarthritis. We have now investigated whether changes in peptide content are reflected in altered neuropeptide gene expression and the time course involved. Using in situ hybridization we found marked increases in expression of beta-preprotachykinin (PPT; 81 +/- 24% rise) and alpha-CGRP (44 +/- 6% rise) mRNAs in innervating (ipsilateral L5) DRG neurones only. These increases occurred at the onset of acute inflammation (8 h) and persisted until chronic arthritis developed after 14 days. There were no changes in the proportion of DRG neurones expressing PPT or CGRP mRNAs. Messenger RNA encoding vasoactive intestinal polypeptide (VIP) was not induced. These data suggest that increased synthesis of PPT and CGRP peptides in DRG may play a role in the pathogenesis both of adjuvant-mediated acute inflammation and chronic arthritis.
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PMID:Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. 128 Dec 53

The nature and distribution of preprotachykinin (PPT, i.e. substance P/neurokinin A-encoding) gene expression in human basal ganglia was determined. Northern blot analysis visualized a single band of approximately 1300 bases, confirming the postmortem stability of PPT mRNA. Gross anatomical analysis indicated that PPT gene expression was relatively evenly distributed throughout the human caudate and putamen, but absent in the globus pallidus and substantia nigra. Nuclease protection analysis of these tissues established that human PPT mRNA consisted of approximately 80-85% beta-PPT (exon 1-7 derived) mRNA and 15-20% gamma-PPT (minus exon 4), with no alpha-PPT (minus exon 6) mRNA detected; these data contrast with the proportions of PPT mRNAs seen in non-human species. The incompletely spliced PPT RNA species detected in basal ganglia accounted for approximately 8% of total human PPT RNA and suggested a fixed order of exon splicing. Since various PPT mRNAs encode different combinations of tachykinin peptides with distinct biological activities, the markedly different proportions of PPT mRNAs seen in human basal ganglia compared to non-human tissues may be of physiological significance.
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PMID:Preprotachykinin gene expression in the human basal ganglia: characterization of mRNAs and pre-mRNAs produced by alternate RNA splicing. 131 3

Purification and potential tachykinin and enkephalin precursor cleaving enzymes from bovine chromaffin granules was undertaken using as substrates the model precursors 35S-(Met)-beta-preprotachykinin [35S-(Met)-beta-PPT] and 35S-(Met)-preproenkephalin [35S-(Met)-PPE]. Purification by concanavalin A-Sepharose, Sephacryl S200, and chromatofocusing resulted in a chromaffin granule aspartyl protease (CGAP) that preferred the tachykinin over the enkephalin precursor. CGAP was composed of 47-, 30-, and 16.5-kDa polypeptides migrating as a single band in a nondenaturing electrophoretic gel system, and coeluting with an apparent molecular mass of 45-55 kDa by size-exclusion chromatography. These results suggest that two forms exist: a single 47-kDa polypeptide and a complex of 30 + 16.5-kDa-associated subunits. CGAP was optimally active at pH 5.0-5.5, indicating that it would be active within the acidic intragranular environment. Cleavage at basic residues was suggested by HPLC and HVE identification of 35S-(Met)-NKA-Gly-Lys as the major acid-soluble product generated from 35S-(Met)-beta-PPT. Neuropeptide K was cleaved at a Lys-Arg basic residue site, as determined by identification of proteolytic products by microsequencing and amino acid composition analyses. Structural studies showed that the three CGAP polypeptides were similar to bovine cathepsin D in NH2-terminal sequences and amino acid compositions, indicating that CGAP appears to be a cathepsin D-related protease or cathepsin D itself. The 47- and 16.5-kDa polypeptides of CGAP possessed identical NH2-terminal sequences, suggesting that the 16.5-kDa polypeptide may be derived from the 47-kDa form by proteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Purification and characterization of a cathepsin D protease from bovine chromaffin granules. 156 70

Using an efficient Escherichia coli expression system, we have been able to obtain the precursor of substance P, alpha-preprotachykinin (alpha PPT). The alpha PPT protein is produced in E. coli as a fusion to beta-galactosidase, and accumulates in the cytoplasm as insoluble inclusion bodies. We also produced protachykinin (alpha PT), i.e., alpha PPT without a signal peptide. Further purification and characterization of the alpha PPT and alpha PT polypeptides strongly suggest that fully purified products can be obtained using our procedures.
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PMID:Synthesis of a gene encoding bovine substance P precursors and its expression in Escherichia coli. 163 73

The presence of N-terminally extended forms of neurokinin A has recently been reported in the mammalian brain. Among them, gamma-preprotachykinin-(72-92)-peptide amide [gamma-PPT-(72-92)-NH2], a peptide derived by posttranslational processing of gamma-preprotachykinin, is most prominent. We report here that this peptide most likely acts on neurokinin-2 receptor sites since neurokinin A (a putative neurokinin-2 agonist) and gamma-PPT-(72-92)-NH2 are potent competitors of 125I-labeled gamma-PPT-(72-92)-NH2 binding whereas selective neurokinin-1 and -3 agonists are not. Moreover, the distribution of 125I-labeled gamma-PPT-(72-92)-NH2 and 125I-labeled neurokinin A binding sites are very similar in rat brain. On the other hand, 125I-labeled Bolton-Hunter-substance P (a neurokinin-1 ligand) and 125I-labeled Bolton-Hunter-eledoisin (a neurokinin-3 ligand) binding sites are differentially located in this tissue. Thus, it appears that gamma-PPT-(72-92)-NH2 binds to neurokinin-2 receptors and should be considered as a putative endogenous ligand for this receptor class.
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PMID:gamma-Preprotachykinin-(72-92)-peptide amide: an endogenous preprotachykinin I gene-derived peptide that preferentially binds to neurokinin-2 receptors. 168 55

In order to study the regulation of co-localized monoamine and peptide neurotransmitters in the medullary raphe nuclei (MRN), we determined whether inhibition of serotonin (5-HT) synthesis affected levels of preprotachykinin (PPT; the prohormone precursor of substance P) mRNA in the MRN. Adult rats received p-chlorophenylalanine (pCPA), an irreversible inhibitor of tryptophan hydroxylase (TPH), via Alzet minipumps. TPH activity was inhibited by 70-80% for 3 weeks following pump implantation. During this period Northern mRNA analysis revealed that PPT mRNA levels in the MRN were increased 1.5-2-fold. The pCPA-induced increase was specific for PPT mRNA since no change was detected in mRNA coding for neuron-specific enolase (NSE; a constitutive neuronal protein) or 28 S ribosomal RNA. To determine whether fetal inhibition of 5-HT synthesis affected development of PPT mRNA in the MRN, pregnant rats were administered pCPA via Alzet minipump implanted on embryonic day 8. In pCPA-treated litters TPH activity was decreased by 60-70% from E16 to postnatal day 3 (P3), returning to control levels by P8. Northern mRNA analysis revealed that PPT mRNA levels increased 2.4-fold of control levels at P1. Infusion of pCPA for one week resulted in an earlier increase in PPT mRNA levels, suggesting that birth was not required to elicit the surge in PPT message. These results support the hypothesis that alterations in 5-HT metabolism have regulatory consequences for co-localized substance P formation in the MRN.
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PMID:Tryptophan hydroxylase inhibition increases preprotachykinin mRNA in developing and adult medullary raphe nuclei. 169 45

Serotonin (5-HT) neurotransmission was altered to determine its role in regulating the biosynthesis of tachykinins in the neostriatum (NS). Depletion of 5-HT with subchronic p-chlorophenylalanine (pCPA) treatment decreased preprotachykinin (PPT, the prohormone precursor to SP) mRNA levels in the NS. By contrast, raising extracellular 5-HT levels with zimelidine (a 5-HT uptake inhibitor) or clorgyline (a monoamine oxidase inhibitor) resulted in increased levels of PPT mRNA. To determine whether 5-HT receptors played a role in mediating the changes in PPT mRNA, animals were treated with the 5-HT2 agonist DOI. This drug significantly increased both PPT mRNA and SP-like immunoreactivity in the NS. These results together indicate that neostriatal tachykinin biosynthesis is sensitive to alterations in 5-HT neurotransmission.
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PMID:Serotonin regulation of tachykinin biosynthesis in the rat neostriatum. 171 19

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

In order to determine whether dopamine mediates the effects of serotonin on tachykinin biosynthesis in the neostriatum, serotonin neurotransmission was altered following depletion of dopamine. Neonatal rats received intracisternal injections of saline or the dopamine neurotoxin 6-hydroxydopamine (6HD). This lesion caused significant reductions in the neostriatum of substance P-like immunoreactivity as well as levels of mRNA coding for preprotachykinin (PPT; the prohormone precursor to tachykinins substance P, neurokinin A and related peptides). Two months later, rats were treated for 5-6 days with saline or the serotonin-uptake inhibitor, zimelidine. Zimelidine treatment of unlesioned animals significantly increased PPT mRNA levels in the neostriatum. However, zimelidine treatment failed to increase PPT mRNA content in 6HD-treated animals. By contrast, neostriatal substance P-like immunoreactivity was restored by zimelidine treatment of 6HD-lesioned animals. These results suggest that an intact nigrostriatal pathway may be required for serotonin neurotransmission to alter PPT mRNA levels in the neostriatum. However, neostriatal tachykinins may be regulated by direct serotonin innervation.
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PMID:Serotonin regulation of neostriatal tachykinins following neonatal 6-hydroxydopamine lesions. 172 Sep 96

The neurons which synthesize tachykinins in the capsaicin-sensitive afferent nerves of the respiratory tract are largely localized to the nodose ganglia. Using a radiolabelled antisense cRNA probe constructed from cDNA for the major precursor of substance P and neurokinin A (beta-preprotachykinin: beta-PPT), we have localized specific mRNA for this peptide in neurons of the nodose ganglion of rat using in situ hybridization. 26% of neurons gave a positive hybridization signal, which was in agreement with the same proportion of cell bodies showing substance P-like immunoreactivity. The specificity of the hybridization was confirmed by the absence of labelling using RNase pre-treatment and a sense probe having the same sequence as beta-PPT mRNA. This approach may now allow the investigation of factors which regulate synthesis of tachykinins at a gene transcriptional level.
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PMID:Localization of beta pre-protachykinin mRNA in nodose ganglion. 172 84


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