Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of two monoclonal antibodies for use as second antibodies in immunocytochemistry is described. The antibodies are produced by mouse X mouse hybrid myelomas, and are both of the IgG type. The two antibodies, RB23 and ND13, were used to detect neurophysin by three-step peroxidase-antiperoxidase (PAP) immunostaining, and were "internally labeled" with 3H-lysine for the radioimmunocytochemical localization of neurophysin, substance P, and tyrosine hydroxylase using rabbit first antibodies. The binding sites of RB23 and ND13 on the rabbit IgG antibodies were determined by solid-phase radioimmunoassay, using allotype-specific rabbit serum to compete with RB23 and ND13. It was found that both RB23 and ND13 are directed against the B4 kappa-light-chain allotype. The immunocytochemical localization of adrenocorticotropic hormone and somatostatin with rabbit primary antibodies was not achieved with RB23 or ND13, and it is proposed that these antibodies are not of the B4 allotype. The findings demonstrate that monoclonal second antibodies can be useful general reagents for conventional immunocytochemistry as well as for radioimmunocytochemistry. Furthermore, allotype-specific monoclonal second antibodies may prove useful in the simultaneous immunohistochemical localization of more than one antigen in a given tissue section.
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PMID:Immunocytochemistry with monoclonal anti-immunoglobulin as a developing reagent: application to immunoperoxidase staining and radioimmunocytochemistry. 641 91

Intracellular recordings were made from isolated left or right stellate ganglia of Wistar rats and the morphology of neurones studied after intracellular injection of hexammine cobaltic chloride or back-filling from the post-ganglionic nerve with cobalt lysine complex. The experiments attempted to identify the location, electrophysiological properties, morphology and chemosensitivity of putative cardiac neurones in the ganglion. These were identified by antidromic activation of the axon in a cardiac nerve and compared with neurones projecting towards the brachial plexus (non-cardiac neurones). Putative cardiac neurones were localized in the ganglion around the postganglionic nerve entry zone and showed considerable morphological diversity. They had complex dendritic trees with, on average, seven dendrites. They included both phasic and tonic neurones and were depolarized by muscarinic agonists, angiotensin and substance P; they invariably had a synaptic input from the sympathetic trunk and from a T1 or T2 ramus and, in 16% of cells, from a cardiac nerve. Non-cardiac neurones were more widely scattered through the stellate ganglion but were not clearly different in morphology, resting membrane potential or the proportion of phasic and tonic cells from putative cardiac neurones. They also showed depolarizing responses to muscarinic agonists, angiotensin and substance P. Angiotensin responses of stellate ganglion cells were blocked by the peptide antagonist, saralasin (1 microM).
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PMID:Properties of putative cardiac and non-cardiac neurones in the rat stellate ganglion. 751 22

As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-[N2-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenyl-methyl) -L- phenylalaninamide (2b). The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in [3H]SP binding assay using guinea pig lung membranes. Next we modified the 1H-indol-3-ylcarbonyl part in 3h. Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity. Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.
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PMID:Studies on neurokinin antagonists. 4. Synthesis and structure-activity relationships of novel dipeptide substance P antagonists: N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl]-N- methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and its related compounds. 751 2

The study of large-scale rearrangements of [b']2+ ions produced by electrospray ionization of Substance P (Tang et al., Anal. Chem. Vol. 65, p. 2824 (1993)) has been extended to 18 other peptides containing either a lysine or ornithine residue remote from the C-terminus. Evidence for wholesale transfer of one or more residues, from the C-terminus of the [b']2+ precursor to the omega-amino group of the Lys (or Orn) residue, was observed for 12 of the 18 peptides studied. Unfortunately, no rigorous predictive rules, relating features of the peptide sequence to the propensity to undergo such rearrangements, could be discerned although a significant correlation with presence of a proline residue close to the lysine or ornithine on the C-terminal side was apparent. The resulting mass-shifts can complicate derivation of peptide sequences from fragment-ion spectra of [M + 2H]2+ peptide ions, for example, since the cyclized [b']2+ ions responsible for the rearrangements are readily formed as intermediate species in the fragmentation mechanisms.
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PMID:Rearrangements of doubly charged acylium ions from lysyl and ornithyl peptides. 752 6

Homogenates of chick dorsal root ganglia (DRG) and in vitro cultures of DRG neurons are known to synthesize prostaglandin (PG) D2. To specify the PGD synthase isozymes controlling PGD2 synthesis in DRG and to identify the DRG cells responsible for this synthesis, we applied polyclonal antibodies raised against rat brain or rat spleen PGD synthase isozymes to vibratome or cryostat slices of DRG previously fixed with a formaldehyde-lysine-periodate mixture and permeabilized with Triton X-100. The immunoreactivity indicating rat spleen PGD synthase, a glutathione (GSH)-requiring enzyme, was located in satellite cells encompassing particular large neurons of class A and in Schwann cells myelinating and enwrapping their initial axonal segments. In contrast, the immunoreactivity of rat brain PGD synthase, a GSH-independent enzyme, was restricted to particular ganglion cell perikarya: 33% of the DRG neurons were immunostained for rat brain PGD synthase, including 2% of large class A neurons and 40% of small class B neurons. Only 3.3% of rat brain PGD synthase-immunoreactive small B neurons coexpressed substance P, indicating that the immunoreactive neurons belong to the B1 subclass. By electron microscopy, 71 of 72 immunoreactive DRG cells were identified as small B neurons of the B1 subclass, and 71 of 77 B1 neurons were immunoreactive for rat brain PGD synthase. These results demonstrate that PGD2 formation in DRG is regulated by two isozymes: the GSH-requiring isozyme located in satellite and Schwann cells and the GSH-independent isozyme-confined to small B1 neurons.
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PMID:Neuronal and glial prostaglandin D synthase isozymes in chick dorsal root ganglia: a light and electron microscopic immunocytochemical study. 752 29

The neurokinin-1 tachykinin receptor is a member of the G protein-coupled receptor superfamily. An unusual feature of the neurokinin-1 receptor is the presence of glutamic acid (residue 78) in the second putative transmembrane domain, at the location of a highly conserved aspartate residue in the G protein-coupled receptor superfamily. The rat neurokinin-1 receptor cDNA was mutated to lysine, aspartate, and glutamine at this site and functionally expressed in Chinese hamster ovary cells, and clonal cell lines were isolated and characterized. Radioligand binding demonstrated that the Asp78 and Lys78 receptors have substance P binding affinities indistinguishable from those of the wild-type receptor and are expressed at roughly the same number of receptors per cell. The Gln78 receptor variant, on the other hand, exhibited no detectable agonist binding. Although wild-type and Asp78 receptors have essentially the same ability to stimulate inositol phospholipid turnover, cAMP production, and arachidonic acid release, the Lys78 variant is markedly attenuated in its ability to activate any of these pathways. These data indicate that residue 78 plays a role in the coupling of the rat neurokinin-1 receptor to cellular effectors. In addition, both Asp78 and Lys78 receptors show a greater percentage of high affinity binding that is resistant to guanosine-5'-O-(3-thio)triphosphate than does the wild-type receptor, indicating a potential difference in G protein coupling between wild-type and mutated receptors.
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PMID:Residue 78 in the second transmembrane domain of the neurokinin-1 receptor is important in coupling high affinity agonist binding to multiple second messenger responses. 753 94

The anti-inflammatory and analgesic profile of a new topical foam formulation of ketoprofen lysine salt (CAS 57469-78-0, Artrosilene Schiuma, KLS-foam) was characterized in comparison with marketed gel formulations containing KLS (KLS-gel) or diclofenac diethylammonium salt (DCF-gel). KLS-foam dose-dependently inhibited oedema formation and hyperalgesia induced by subplantar injection of carrageenan or substance P, being more potent than KLS-gel. At equieffective anti-inflammatory doses, KLS-foam provided a more pronounced analgesic effect than DCF-gel. KLS-foam also markedly inhibited exudate formation and prostaglandin production induced by subcutaneous implantation of carrageenan soaked sponges. In carrageenan induced paw inflammation, KLS-foam provided the same anti-inflammatory effect as orally administered KLS, but induced significantly less gastric damages. Oral administration of KLS resulted in sustained systemic absorption of ketoprofen, whereas after topical application of KLS-foam no appreciable ketoprofen plasma levels were detected. These data support the anti-inflammatory and particularly the analgesic effectiveness of the new foam formulation of KLS, a finding that, together with the high gastric tolerability, further emphasizes the usefulness of KLS-foam in the treatment of localized flogistic diseases and associated pain.
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PMID:Effects of a new foam formulation of ketoprofen lysine salt in experimental models of inflammation and hyperalgesia. 754 96

As an extension of our study on discovering a novel substance P (SP) antagonist, we designed new branched tripeptides containing L-aspartic acid (2 and 5), L-ornithine (3 and 6), and L-lysine (4 and 7) by reconstructing the structure of the previously reported tripeptide SP antagonist [Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (1), FR113680]. The strategy for this design was based on the postulate that the dipeptide half D-Trp(CHO)-Phe-NMeBzl in 1 is essential for receptor recognition. Molecular modeling studies implied that these newly designed tripeptides could mimic the spatial orientations of the essential dipeptide structure. As expected, all of these compounds potently inhibited 3H-SP (1 nM) binding to guinea pig lung membranes in the 10(-8) M range. The 1H-indol-3-ylcarbonyl derivatives (5-7) were slightly more potent than the corresponding 1H-indol-2-ylcarbonyl derivatives (2-4), as predicted by the molecular modeling studies. The structure-activity relationships studies on the selected 1H-indol-3-ylcarbonyl derivatives indicated that the threonine moiety at the side chain can be modified into a variety of structures without any significant loss of the activity. Furthermore in the L-lysine series, even dipeptide compounds having nothing or a simple acyl group at the epsilon-amino group, such as N alpha-[N alpha-(1H-indol-3-ylcarbonyl)-L-lysyl]-N-methyl-N-(phenylmethyl)- L-phenylalaninamide (18b), exhibited potent activity. These dipeptides belong to a new structural class of SP antagonist.
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PMID:Studies on neurokinin antagonists. 3. Design and structure-activity relationships of new branched tripeptides N alpha-(substituted L-aspartyl, L-ornithyl, or L-lysyl)-N-methyl-N-(phenylmethyl)-L-phenylalaninamides as substance P antagonists. 768 52

Hepatitis C virus (HCV) encodes a polyprotein that is processed to produce the structural and nonstructural proteins of the virus. Nonstructural protein 3 (NS3) is a serine proteinase that cleaves the polyprotein to release the NS4A, NS4B, NS5A, and NS5B proteins. To characterize the substrate specificity of NS3, we synthesized by in vitro translation the polyprotein NS2*-NS3-NS4*P that includes 70% of the NS2 protein, the complete NS3 protein, and 25% of the NS4 protein region attached to substance P, an epitope tag. We demonstrated that NS3 cleaves at the NS3/NS4A junction to release the NS4*P protein. Subsequently, we used this reaction to evaluate the importance of conserved amino acids that flank the NS3/NS4A junction. We replaced amino acids in the P6, P1, and P1' positions of the scissile bond of this junction using site-directed mutagenesis. When the P6 aspartic acid was changed to asparagine, lysine, or serine, NS3-mediated cleavage occurred. When threonine in the P1 position was replaced with other polar amino acids or with amino acids having aliphatic side chains, cleavage occurred, although it was not detected when arginine or tyrosine was present. Replacement of serine in the P1' position with other polar amino acids, with amino acids having aliphatic side chains, or with arginine resulted in NS3-mediated cleavage. Thus, since fewer amino acids in the P1 position supported cleavage than in the P6 or P1' positions, the P1 position of the scissile bond may play a more important role in defining the substrate specificity of the HCV NS3 proteinase.
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PMID:Substrate specificity of the NS3 serine proteinase of hepatitis C virus as determined by mutagenesis at the NS3/NS4A junction. 809 50

A dose-dependent immunomodulating effect of synthetic low-molecular weight peptides was found in CBA mice. Talcin and its analogue, rigin, tripeptide SKE, substance P and its analogue, and vasopressin were shown to produce an immunostimulating effect, whereas vasopressin tetrapeptide, arginyl-asparagine, and tripeptide SKD showed an immunosuppressive effect. The immunomodulatory effect of the peptides tested was associated with the presence of amino acids such as arginine, lysine, tyrosine, glutamic acid in their chemical structure. These amino acids are essential in the mechanisms of immune responses.
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PMID:[The peptide modulation of immune reactions]. 832 77


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