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)

Two hexapeptides related to the undecapeptide substance P (SP) Glu-Phe-Phe-Gly-Leu-Met-NH2 and Glu-Phe-Phe-Pro-Leu-Met-NH2, have been synthesized and their selectivity for the SP receptors studied. Conformational analyses of both peptides have been carried out using a molecular modeling program. Activity appears to be related to the adoption of a U-shape conformation since the Pro9 containing peptide in which this folding is favoured is much more active than the hexapeptide containing Gly9. Moreover, such a substitution induces a significant selectivity for the SP-P receptor compared to the SP-E receptor.
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PMID:Conformation-activity relationship in hexapeptides related to substance P. 247 88

The effects of calcitonin gene-related peptide (CGRP) on canine cerebral arteries and on vertebral blood flow were investigated in-vivo and in-vitro and the findings compared with the effects of vasoactive intestinal peptide (VIP) and substance P. Administration of CGRP into the vertebral artery caused a dose-dependent and long-lasting increase in blood flow. The in-vivo vasodilatory effects of substance P and VIP were short-lasting. CGRP (0.1 to 100 nmol/l) elicited a concentration-dependent relaxation of the isolated middle cerebral and basilar arteries when the tissues were precontracted by exposure to prostaglandin F2 alpha (PGF2 alpha). This effect was not antagonized by propranolol, atropine, tetrodotoxin, (N-Ac-Tyr1, D-Phe2)-growth hormone-releasing factor(1-29)-NH2 or (D-Pro2, D-Trp7,9) substance P. CGRP also reduced concentration-dependently the contraction of cerebral arteries induced by KCl or 9,11-epithio-11,12-metano-thromboxane A2 (STXA2). Mechanical removal of the endothelium did not abolish the vasodilatory response to CGRP. In PGF2 alpha-contracted canine cerebral arteries, VIP (0.1 to 100 nmol/l) was less potent a vasodilator than CGRP. At low concentrations (0.01 to 1 nmol/l) substance P elicited a rapid and short-lasting relaxation, and in the absence of endothelium this relaxation disappeared. These findings are clear evidence that CGRP modulates vascular tone.
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PMID:Effects of calcitonin gene-related peptide on canine cerebral artery strips and the in-vivo vertebral blood flow in dogs. 247 44

Dimeric analogs of neurokinin A and neurokinin B COOH-terminal heptapeptides were synthesized in order to examine the effect of ligand dimerization on the receptor selection. Dimerization was carried out at the NH2-terminus of peptides with succinic acid, yielding succinyl bis[Asp-Ser-Phe-Val-Gly-Leu-Met-NH2] (D-NKA4-10) and succinyl bis[Asp-Phe-Phe-Val-Gly-Leu-Met-NH2] (D-NKB4-10). In the assay using rat vas deferens (RVD), it was found that the deletion of the NH2-terminal tripeptide from native neurokinin A or B enhances the activity 1.5- to 8-fold, resulting in formation of NK-2 receptor specific ligands NKA4-10 and NKB4-10. When dimeric analogs of these shortened peptides, namely D-NKA4-10 and D-NKB4-10, were examined in RVD and guinea pig ileum (GPI), they were fairly potent in GPI, but not in RVD. Under conditions in which the NK-1 receptors in GPI were desensitized with NK-1 specific substance P methyl ester, dimers reduced the activity drastically, while the corresponding monomers exhibited unchanged activity. These results suggest that dimerization of the COOH-terminal heptapeptide of neurokinins changes the receptor selection of peptides from NK-2 to NK-1, and that the NK-1 receptor has a structure favorable to a dimeric peptide ligand.
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PMID:Design and synthesis of dimeric analogs of neurokinin A and B: effect of dimerization of COOH-terminal heptapeptides on receptor selection. 248 10

This report summarizes the recent rapid development of research on neutral endopeptidase 24.11 (enkephalinase; NEP) and on two other metalloenzymes, meprin and endopeptidase 24.15. NEP cleaves a variety of active peptides, including enkephalins, at the amino side of hydrophobic amino acids. The cDNA for human, rat, and rabbit NEP has been cloned and the deduced protein sequences revealed a high degree of homology (93-94%). Site-directed mutagenesis proved that an active site glutamic acid is involved in catalysis and two active site histidines are responsible for binding the zinc cofactor. Although NEP was originally discovered in the kidney, it is widely distributed in the body including specific structures in the central nervous system, lung, male genital tract, and intestine and in neutrophils, fibroblasts, and epithelial cells. In tissues and cells NEP is bound to plasma membrane through a hydrophobic membrane-spanning domain near the NH2 terminus, but it is present in soluble form in urine and blood. In addition to enkephalins, NEP cleaves kinins, chemotactic peptide, atrial natriuretic factor (ANF), and substance P in vivo. NEP in the lung is a major inactivator of substance P, which constricts the airway smooth muscles. Because of the possible involvement of NEP in the metabolism of opioid peptides and the cardiac hormone ANF, orally active inhibitors have been synthesized. Compounds that inhibit both aminopeptidase and NEP were reported to prolong the analgesic effects of enkephalins. Other inhibitors given per os prolonged the renal effects of exogenous ANF. A newly synthesized specific inhibitor of NEP was also active in animal experiments as an analgesic. Studies on the structure and function of NEP should lead to further development of therapeutically applicable inhibitors.
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PMID:Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. 252 10

Binding of atrial natriuretic peptide (ANP) to rat submandibular gland and its effect on guanosine 3',5'-cyclic monophosphate (cGMP) formation and salivary secretion were investigated. Membranes rapidly and specifically bound 125I-ANP. Binding was inhibited by unlabeled ANP (IC50 approximately 1.6 nM), but not by atriopeptin I, other COOH- and NH2-terminal deleted ANP fragments, or agents such as pilocarpine or substance P. Scatchard analysis revealed a single class of high-affinity sites (dissociation constant 0.74 +/- 0.25 nM; maximal binding capacity 20.5 +/- 6.3 pmol/mg protein). Intravenous infusion of ANP with pilocarpine caused a significant dose-dependent increase in the levels of cGMP detected in plasma and saliva. Because salivary cGMP may have originated in plasma, the effect of ANP on cGMP formation was evaluated in dispersed cells. ANP evoked a concentration-dependent increase in both cGMP synthesis and secretion (EC50 approximately 1.7 x 10(-8) M). The atrial peptide did affect basal or l-isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate synthesis in dispersed cells. When infused by itself and/or with pilocarpine, ANP did not alter the rate of spontaneous or pilocarpine-induced salivary flow, secretion of chloride, or protein release. The data demonstrate the presence of guanylate cyclase-coupled ANP receptors in submandibular gland; the atrial peptide, however, does not exert an effect of the secretory function of the gland.
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PMID:Atrial natriuretic peptide stimulates submandibular gland synthesis and secretion of cGMP. 255 37

Three new cyclic substance P analogues were prepared to examine the possible role of a pseudocyclic turn structure for receptor recognition. In the guinea pig isolated ileum [Cys5, Cys11]-SP5-11-NH2 and [Cys6, Cys11]-SP5-11-NH2 were inactive at concentrations up to 100 microM, while [Cys5, Cys6, Nle11]-SP was a weak agonist. The order of relative affinities on the rat brain radioreceptor assay was as follows: [Cys5, Cys6, Nle11]-SP greater than [Cys5, Cys11]-SP5-11-NH2 greater than [Cys6, Cys11]-SP5-11-NH2. We interpret these results to indicate that a pseudocyclic structure of the 5-11 sequence may not be an important factor involved in the receptor recognition of substance P.
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PMID:Conformationally restricted cyclic analogues of substance P: insight into the receptor binding process. 257 58

The presence of gastrin-releasing peptide-like immunoreactivity in the rat brain was investigated by use of the indirect peroxidase-antiperoxidase technique. A high density of gastrin-releasing peptide-like immunoreactive terminals in the ventral pallidum, the interpenduncular nucleus and in substantia nigra, pars reticulata, was observed. Moreover, gastrin-releasing peptide-like immunoreactive perikarya were observed in the hypothalamic suprachiasmatic nucleus. Antisera raised against gastrin-releasing peptide have been shown to cross-react with substance P, another peptide highly concentrated in the substantia nigra, the ventral pallidum and the interpenduncular nucleus, and gastrin-releasing peptide-immunoreactivity in these areas has therefore been regarded as substance P immunoreactivity. To determine the antigenic epitope recognized by the antiserum raised against gastrin-releasing peptide, specificity studies were performed with known peptides fixed to nitrocellulose filter strips as well as preabsorptions with the same peptides on fixed brain sections containing the substantia nigra. From these experiments, it could be deduced that the antiserum recognizes an epitope within the peptide sequence: Val-Gly-His-Leu-Met-NH2. The antiserum cross-reacts with bombesin and alytesin, but not with substance P, allowing us to conclude that gastrin-releasing peptide or a very closely related peptide is present in areas of the rat central nervous system in which substance P has previously also been shown to be present.
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PMID:An immunohistochemical demonstration of gastrin-releasing peptide (GRP) in the rat substantia nigra. 260 12

Neurons with intrinsic pacemaker activity and presumed sympathoexcitatory function were recorded in rat tissue slices within the confines of the rostroventrolateral reticular nucleus (RVL). These cells were excited in dose-dependent fashion by arginine vasopressin (AVP, 10(8)-10(6) M) but not by oxytocin (up to 10(7) M). The effect of AVP was mimicked by the V1-selective agonist [Phe2,Orn8]vasotocin (VT) (1 microM) but not by the V2-agonist [Val4,D-Arg8]vasopressin (VP) (1.9 microM). The effect of AVP (10(-7) M) was completely blocked by SKF 101926 (10(7) M), a non-selective antagonist and by d(CH2)5[Tyr(Me)2]AVP, a V1-selective antagonist but was unaffected by the V2-selective antagonist d(CH2)5[D-Ile2,Ile4,Ala-NH2 9]AVP. These cells were also activated by thyrotropin-releasing hormone (TRH) (10(-7)-10(-6) M), calcitonin gene-related peptide (CGRP) (4 X 10(-8) M), substance P, (10(-6) M), neuropeptide Y (NPY) (10(-8) M) and inhibited by Met-enkephalin (10(-6) M) and morphine (2 mM). Corticotropin-releasing factor (CRF) (10(-7) M) and angiotensin II (10(-6) M) were ineffective. In conclusion, RVL pacemaker neurons have vasopressin receptors reminiscent of the V1 (vascular and pressor) subtype. Their pacemaking activity is modulated by low doses of several other peptides also known to produce large vasomotor effects after introduction into the cerebroventricular space.
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PMID:Effects of vasopressin and other neuropeptides on rostral medullary sympathoexcitatory neurons 'in vitro'. 275

Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (F-8-NH2) is a peptide, originally detected by FMRF-NH2 antisera, and subsequently isolated from bovine brain. Using a specific radioimmunoassay for F-8-F-NH2, we have examined the regional distribution and characteristics of F-8-F-NH2 immunoreactivity (IR) in rat brain, spinal cord and pituitary gland. In CNS, F-8-F-NH2-IR is highly concentrated in the spinal cord, hypothalamus and pons-medulla (368, 202 and 136 fmol per mg protein, respectively); lowest values are in the cortex and hippocampus. A modest rostrocaudal gradient of F-8-F-NH2-IR was observed; levels in the sacral cord are 50% higher than in the cervical cord. Dorsal cord content is 8 times higher than in the ventral cord. Dorsal rhizotomy failed to change F-8-F-NH2-IR in the affected regions of the spinal cord while significantly reducing substance P levels. F-8-F-NH2-IR was significantly decreased caudal to a spinal transection, indicating the presence of a descending pathway within the spinal cord. The highest concentration of F-8-F-NH2-IR (1008 fmol per mg protein) was found in the neurointermediate lobe of the pituitary, while no F-8-F-NH2-IR could be detected in the anterior lobe. Immunohistochemically, F-8-F-NH2-IR was confined to nerve terminal-like structures in the neural lobe. The anterior and intermediate lobes were devoid of immunoreactive structures. HPLC characterization of F-8-F-NH2-IR in the dorsal spinal cord, medulla-pons and pituitary revealed one major immunoreactive peak which is more hydrophobic than bovine F-8-F-NH2. In addition to this material, the hypothalamus was found to contain another, more abundant F-8-F-NH2-immunoreactive peak. Analysis of F-8-F-NH2-IR from posterior pituitary with various antisera having differing affinities for F-8-F-NH2 and gamma 1-MSH indicates that the F-8-F-NH2-IR of rat pituitary is not due to gamma 1-MSH. The high concentration of F-8-F-NH2-like peptide in the dorsal spinal cord supports a role in mediating nociceptive transmission while the localization of F-8-F-NH2-IR in the posterior pituitary suggests an additional autonomic or endocrine function.
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PMID:Rat brain regional distribution and spinal cord neuronal pathway of FLFQPQRF-NH2, a mammalian FMRF-NH2-like peptide. 276 8

An N-terminally directed antiserum to neurokinin B was raised in rabbits using an immunogen prepared by coupling the free-SH group of neurokinin B extended from its C-terminus by a cysteine residue (NKB-Cys) to an -NH2 group on human serum albumin using a heterobifunctional cross-linking reagent. In radioimmunoassay with 125I-Bolton-Hunter-labelled NKB-Cys as tracer, the antiserum showed no cross-reactivity with other tachykinins. An extract of a human pheochromocytoma, previously shown to contain peptides derived from preprotachykinin A, contained NKB-LI (13 pmol/g wet weight). The retention time of tumor neurokinin on reversed-phase HPLC was the same as that of synthetic neurokinin B. Peptides with the retention times of substance P, neurokinin A, neurokinin A (3-10)-peptide and neuropeptide K were also identified in the tumor extract. NKB-LI was not detected in extracts of a further nine pheochromocytomas or in five carcinoid tumors that expressed the preprotachykinin A gene.
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PMID:Neurokinin B in a human pheochromocytoma measured with a specific radioimmunoassay. 278 Apr 25


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