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)

Somatostatin (SRIF) binding sites were characterized in goldfish brain. Binding of (125)I-[Tyr(11)]-SRIF-14 to a brain membrane preparation was found to be saturable, reversible, and time-, temperature-, and pH-dependent. Binding was also displaceable by different forms of SRIF. Under optimal conditions (22 degrees C, pH 7.2), the equilibrium binding of (125)I-[Tyr(11)]-SRIF-14 to goldfish brain membranes was achieved after 60 min incubation. Analysis of saturable equilibrium binding revealed a one-site model fit with K(a) of 1.3 nM. SRIF-14, mammalian SRIF-28, and salmon SRIF-25 displaced (125)I-[Tyr(11)]-SRIF-14 binding with similar affinity, whereas other neuropeptides, e.g., substance P, were unable to displace (125)I-[Tyr(11)]-SRIF-14. Autoradiography studies demonstrated that (125)I-[Tyr(11)]-SRIF-14 binding sites are found throughout the goldfish brain. A high density of (125)I-[Tyr(11)]-SRIF-14 binding sites was found in the forebrain, including the nucleus preopticus, nucleus preopticus periventricularis, nucleus anterioris periventricularis, nucleus lateralis tuberis, nucleus dorsomedialis thalami, nucleus dorsolateralis thalami, nucleus ventromedialis thalami, and nucleus diffusus lobi inferioris. In midbrain, (125)I-[Tyr(11)]-SRIF-14 binding sites were found in the optic tectum. The facial and vagal lobes and the mesencephalic-cerebellar tract were found to have a high density of binding sites. This study provides the first characterization and distribution of specific binding sites for SRIF in a fish brain.
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PMID:Characterization and distribution of somatostatin binding sites in goldfish brain. 1062 Apr 28

Receptor targeting with radiolabeled peptides has become very important in nuclear oncology in the past few years. The most frequently used peptides in the clinic are analogs of somatostatin (SRIF), e.g. OctreoScan, which contain chelators for the radioisotopes 111In, 86Y, 90Y, 67Ga, 68Ga and 64Cu or for 99mTc and 188Re. and were labelled with the halogens 123I and 18F. Radiolabeled analogs of &alpha-melanocyte-stimulating hormone (&alpha-MSH), neurotensin, vasoactive intestinal peptide (VIP), bombesin (BN), substance P (SP) and gastrin/cholecystokinin (CCK) are also being developed, evaluated in vitro and in vivo and tested for clinical application. This review focuses on the expression in tumors and the regulation of receptors for these neuropeptides as well as the development of novel chelator-peptide conjugates suitable for in vivo scintigraphy or internal radiotherapy. The state of the art of radiopeptide pharmaceuticals is illustrated with four SRIF analogs, modified with the macrocyclic chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA): [D-Phe1]-octreotide (DOTAOC), [D-Phe1, Tyr3]-octreotide (DOTATOC), vapreotide (DOTAVAP) and lanreotide (DOTALAN). DOTA is almost a universal chelator capable of strongly encapsulating hard metals such as 111In and 67Ga for Single Photon Emission Tomography (SPET), 68Ga, 86Y and 64Cu for Positron Emission Tomography (PET) as well as 90Y for receptor-mediated radionuclide therapy and radiolanthanides which exhibit different interesting decay schemes. From biodistribution studies in experimental animals and from clinical data it is concluded that DOTATOC is currently the most suitable SRIF radiopeptide with the best potential in the clinic.
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PMID:Receptor targeting for tumor localisation and therapy with radiopeptides. 1091 Oct 25

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) has recently been isolated from porcine and rat brain and identified as the endogenous ligand of the N/OFQ receptor (NOP). It shows structural similarity with opioid peptides. N/OFQ has also been demonstrated in the gastrointestinal tract, where it inhibits gastrointestinal motility. The effect of N/OFQ on gastric neuroendocrine function is unknown as yet. In the isolated perfused rat stomach, N/OFQ 10(-6) M shows a small, but not significant decrease of basal somatostatin (SRIF) secretion. At the doses of 10(-12) M, 10(-10) and 10(-8) M N/OFQ has neither an effect on basal SRIF nor on basal vasoactive intestinal polypeptide (VIP), gastrin, substance P or bombesin secretion, respectively. However, gastric inhibitory polypeptide (GIP) 10(-9) M prestimulated SRIF secretion is significantly inhibited by N/OFQ 10(-8) M (-45+/-11%; p<0.05 vs. GIP). During concomitant infusion of the specific competitive NOP receptor antagonist [Nphe(1)]nociceptin(1-13)NH(2) 10(-6) M, the effect of N/OFQ is abolished (6+/-11%; p<0.05 vs. GIP and N/OFQ) while the opiate receptor antagonist naloxone 10(-6) M has no significant effect (-32+/-9%; ns vs. GIP and N/OFQ). At the higher concentration of N/OFQ 10(-6) M, the inhibition of prestimulated SRIF secretion (-58+/-6%; p<0.05 vs. GIP) is not influenced by the NOP receptor antagonist at the concentration of 10(-6) M (-49+/-9%; ns vs. GIP and N/OFQ) and 10(-5) M (-69+/-10%; ns vs. GIP and N/OFQ), respectively. On the other hand, infusion of naloxone 10(-6) M attenuates the inhibitory effect of N/OFQ 10(-6) M significantly (-21+/-6%; p<0.05 vs. GIP and N/OFQ).Thus, N/OFQ is an inhibitor of gastric somatostatin secretion. At the lower dose, this effect is transmitted via NOP receptors, while at the higher dose of 10(-6) M, the effect is at least in part mediated via opiate receptors.
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PMID:Inhibitory effect of nociceptin on somatostatin secretion of the isolated perfused rat stomach. 1213 64

Substance P (SP) and somatostatin (SRIF) are widely spread throughout the CNS where they play a role as neurotransmitters and/or neuromodulators. A colocalization of both neuropeptides has been demonstrated in several rat brain areas and SP receptors have been detected in rat cortical and hippocampal somatostatinergic cells. The present study was thus undertaken to determine whether SP could modulate SRIF signaling pathways in the rat frontoparietal cortex and hippocampus. A single intraperitoneal injection of SP (50, 250 or 500 micro g/kg) induced an increase in the density of SRIF receptors in membranes from the rat frontoparietal cortex at 24 h of its administration, with no change in the hippocampus. The functionality of the SRIF receptors was next investigated. Western blot analysis of Gi proteins demonstrated a significant decrease in Gialpha1 levels in frontoparietal cortical membranes from rats treated acutely (24 h) with 250 micro g/kg of SP, which correlated with a decrease in functional Gi activity, as assessed by use of the non-hydrolyzable GTP analog 5'-guanylylimidodiphosphate. SRIF-mediated inhibition of basal or forskolin-stimulated adenylyl cyclase activity was also significantly lower in the frontoparietal cortex of the SP-treated group, with no alterations in the catalytic subunit of the enzyme. SRIF-like immunoreactivity content was increased in the frontoparietal cortex after acute (24 h) SP administration (250 or 500 micro g/kg) as well as in the hippocampus in response to 7 days of SP (250 micro g/kg) administration. All these SP-mediated effects were prevented by pretreatment with the NK1 receptor antagonist RP-67580. Although the physiologic significance of these results are unknown, the increase in SRIF receptor density together with the desensitization of the SRIF inhibitory signaling pathway might be a mechanism to potentiate the stimulatory pathway of SRIF, inducing a preferential coupling of the receptors to PLC.
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PMID:Modulation of somatostatin receptors, somatostatin content and Gi proteins by substance P in the rat frontoparietal cortex and hippocampus. 1248 11

Although somatostatin (somatotrophin release inhibitory factor; SRIF) is a well-known inhibitory peptide, there are only a few reports of it acting as a positive modulator. In this work, the action of somatostatin upon rat submandibular protein secretion was studied. In vivo somatostatin infusion (35 microg/(kg h)) raised protein secretion stimulated by adrenergic and peptidergic agents. To rule out possible systemic effects of somatostatin, in vitro experiments were performed. Somatostatin (90 nmol/l) augmented protein release stimulated by noradrenaline (19 micromol/l) and substance P (10 micromol/l), but it did not affect isoprenaline (400 micromol/l)-induced protein release. Phenoxybenzamine (20 micromol/l) reduced the effect of somatostatin on noradrenaline-stimulated protein release. Propranolol (20 micromol/l) increased the noradrenaline-stimulated protein release and this effect was synergistic with the action of somatostatin. The absence of extracellular calcium did not significantly reduce somatostatin enhancement of agonist-induced secretion. Fluorescence measurements of the Ca(2+)-sensitive dye fluo3 showed that cytosolic calcium in acinar cells remained elevated during stimuli when somatostatin was present in the medium. It was concluded that somatostatin modulates rat submandibular protein secretion by prolonging the time that the cytosolic calcium signal remains high after stimulus.
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PMID:Modulation by somatostatin of rat submandibular salivary secretion. 1264 58

In our continuing program exploring glucose-based peptidomimetics of somatostatin (SRIF-14), we sought to improve the water solubility of our glycosides. This led to insights into the nature of the ligand binding sites at the SRIF receptor. Replacement of the C4 benzyl substituent in glucoside (+)-2 with pyridinylmethyl or pyrazin-2-ylmethyl congeners increased water solubility and enhanced affinity for the human SRIF subtype receptor 4 (sst4). We attribute this effect to hydrogen bond formation. The pyridin-3-ylmethyl substituent at C4, when combined with the imidazol-4-ylmethyl group at C2, generated (-)-19, which has the highest affinity of a glucose-based peptidomimetic at a human SRIF receptor to date (K(i) 53 +/- 23 nM, n = 6 at sst4). The C4 heterocyclic congeners of glucosides bearing a 1-methoxy substituent rather than an indole side chain at the anomeric carbon, such as (+)-16, also provided information about the Trp(8) binding pocket. We correlated the SARs at both the C4 and the Trp(8) binding pockets with calculations of the electrostatic potentials of the diverse C4 aromatic substituents using Spartan 3-21G(*) MO analysis. These calculations provide an approximate analysis of a molecule's ability to interact within a receptor binding site. Our binding studies show that benzene and indole rings, but not pyridinylmethyl nor pyrazin-2-ylmethyl rings, can bind the hydrophobic Trp(8) binding pocket of sst4. The Spartan 3-21G(*) MO analysis reveals significant negative electrostatic potential in the region of the pi-clouds for the benzene and indole rings but not for the pyridinylmethyl or pyrazin-2-ylmethyl congeners. Our data further demonstrate that the replacement of benzene or indole side chains by heterocyclic aromatic rings typified by pyridine and pyrazine not only enhances water solubility and hydrogen bonding capacity as expected, but can also profoundly diminish the ability of the pi-cloud of the aromatic substituent to interact with side chains of an aromatic binding pocket such as that for Trp(8) of SRIF-14. Conversely, these calculations accommodate the experimental findings that pyrazin-2-ylmethyl and pyridinylmethyl substituents at C4- of C1-indole-substituted glycosides afford higher affinities at sst4 than the C4-benzyl group of (+)-2. This result is consistent with the high electron density in the plane of the heterocycle depicted in Figure 6 which can accept hydrogen bonds from the C4 binding pocket of the receptor. Unexpectedly, we found that the 2-fluoropyridin-5-ylmethyl analogue (+)-14 more closely resembles the binding affinity of (+)-8 than that of (+)-2, thus suggesting that (+)-14 represents a rare example of a carbon linked fluorine atom acting as a hydrogen bond acceptor. We attribute this result to the ability of the proton to bind the nitrogen and fluorine atoms simultaneously in a bifurcated arrangement. At the NK1 receptor of substance P (SP), the free hydroxyl at C4 optimizes affinity.
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PMID:Effects of heterocyclic aromatic substituents on binding affinities at two distinct sites of somatostatin receptors. Correlation with the electrostatic potential of the substituents. 1272 49

(1) Peripheral inflammation causes an increase in the proportion of primary afferent neurones that express neurokinin(1) (NK(1)) receptors for substance P (SP). This upregulation may contribute to the neuronal mechanisms of inflammatory pain. The aim of this study was to identify endogenous mediators that stimulate upregulation of NK(1) receptors in dorsal root ganglion (DRG) neurones. Cultured DRG neurones from the adult normal rat were exposed for 2 days to media that contained specific mediators, namely potassium in high concentration, prostaglandin E(2) (PGE(2)), somatostatin (SRIF), and compounds influencing second messenger cascades. After fixation neurones were labelled with an NK(1) receptor antibody. (2) Repetitive addition of the inflammatory mediator PGE(2) or dibutyryl-cyclic adenosine 3',5' monophophate (db-cAMP) to the culture medium enhanced the proportion of neurones with NK(1) receptor-like immunoreactivity from about 12% up to 40%. PGE(2)-induced upregulation was prevented by coadministration of PGE(2) and a protein kinase A inhibitor or SRIF to the medium. High potassium concentration, protein kinase C inhibitors and omission of nerve growth factor from the medium had no effect. (3) In calcium-imaging experiments, bath application of SP evoked increases of the intracellular calcium concentration in about 20% of the neurones. This proportion increased to about 40% after PGE(2)-pretreatment, but the increase was prevented when PGE(2) and SRIF were coadministered to the medium. (4) These data show that the expression of NK(1) receptor-like immunoreactivity in DRG neurones is regulated by the inflammatory mediator PGE(2). This upregulation depends on the intracellular adenylyl cyclase-protein kinase A pathway.
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PMID:Prostaglandin E2 increases the expression of the neurokinin1 receptor in adult sensory neurones in culture: a novel role of prostaglandins. 1278 27

Rats treated with iminodipropionitrile develop a neurobehaviour syndrome with dyskinesia. Searching for the molecular correlates, we have examined the expression of selected genes involved in neurotransmission in motor regions using hybridization histochemistry. Frontal cortical and thalamic vasoactive intestinal peptide (VIP) expression, and striatal dynorphin, enkephalin (ENK) and substance P expression were increased. No change in cortical cholecystokinin (CCK), ENK, glutamic acid decarboxylase (GAD) and somatostatin (SRIF) expression, in striatal GAD, SRIF, nitric oxide synthase (NOS) and guanylate cyclase expression, and in thalamic CCK, GAD and thyrotropin-releasing hormone expression was found. NOS expression in the subthalamic nucleus as well as tyrosine hydroxylase, GAD and CCK expression in the substantia nigra were unchanged. These results confirm the involvement of striatal projection neurons in dyskinesia and suggest a novel role for VIP.
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PMID:Expression of neurotransmitter genes in motor regions of the dyskinetic rat after iminodipropionitrile. 1286 38

The present review examines various aspects of the developmental expression of neuropeptides and of their receptors in mammalian retinas, emphasizing their possible roles in retinal maturation. Different peptidergic systems have been investigated with some detail during retinal development, including substance P (SP), somatostatin (SRIF), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), opioid peptides and corticotrophin-releasing factor (CRF). Overall, the developmental expression of most peptides is characterized by early appearance, transient features and achievement of the mature pattern at the time of eye opening. Concerning possible developmental actions of neuropeptides, recent studies imply a role of SP in the modulation of cholinergic neurotransmission in early postnatal rabbit retinas, when cholinergic cells participate in the retinal spontaneous waves of activity. In addition, the presence of transient SRIF expressing ganglion cells and recent observations in SRIF receptor knock-out mice indicate variegated roles of this peptide in the development of the retina and of retinofugal projections. Furthermore, VIP and PACAP exert protective and growth-promoting actions that may sustain retinal neurons during their development, and opioid peptides may control cell proliferation in the developing retina. Finally, a peak in the expression of certain peptides, including VIP, NPY and CRF, is present around the time of eye opening, when the retina begins the analysis of structured visual information, suggesting important roles of these peptides during this delicate phase of retinal development. In summary, although the physiological actions of peptides during retinal development are far from being clarified, the data reviewed herein indicate promising perspectives in this field of study.
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PMID:Expression of neuropeptides and their receptors in the developing retina of mammals. 1297 90

The aim of this study was to assess the potential of gastrointestinal peptide plasma levels as biomarkers of radiation-induced digestive tract damage. To this end, plasma levels of substance P, GRP, motilin, PYY, somatostatin-28, gastrin, and neurotensin were followed for up to 5 days in pigs after a 16-Gy whole-body X-irradiation, completed by a histopathological study performed at 5 days. Each peptide gave a specific response to irradiation. The plasma levels of GRP and substance P were not modified by irradiation exposure; neither were those of motilin and PYY. Concerning gastrin, a 2-3-fold increase of plasma concentration was observed in pig, which presented the most important histological alterations of the stomach. The plasma levels of somatostatin, unchanged from 1 to 4 days after irradiation, was also increased by 130% at 5 days. In contrast, a diminution of neurotensin plasma levels was noted, firstly at 1 day (-88%), and from 3 days after exposure (-50%). The present study suggested that changes in gastrin and neurotensin plasma levels were associated with structural alterations of the stomach and ileum, respectively, indicating that they may be relevant biological indicators of radiation-induced digestive damage to these segments.
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PMID:Screening of a large panel of gastrointestinal peptide plasma levels is not adapted for the evaluation of digestive damage following irradiation. 1505 91

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