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)

GH4C1 cells are a clonal strain of rat pituitary tumor cells which synthesize and secrete prolactin and growth hormone. Somatostatin, a hypothalamic tetradecapeptide, inhibits the release of growth hormone and, under certain circumstances, also prolactin from normal pituitary cells. We have prepared [125I-Tyr1]somatostatin (approximately 2200 C1/mmol) and have shown that this ligand binds to a limited number of high affinity sites on GH4C1 cells. Half-maximal binding of somatostatin occurred at a concentration of 6 x 10(-10) M. A maximum of 0.11 pmol of [125I-Tyr1]somatostatin was bound per mg of cell protein, equivalent to 13,000 receptor sites per cell. The rate constant for binding (kon) was 8 x 10(7) M(-1) min(-1). The rate constant for dissociation (koff) was determined by direct measurement to be 0.02 min(-1) both in the presence and absence of excess nonradioactive somatostatin. Binding of [125I-Tyr1]somatostatin was not inhibited by 10(-7) M thyrotropin-releasing hormones. Substance P, neurotensin, luteinizing hormone-releasing hormone, calcitonin, adrenocorticotropin, or insulin. Of seven nonpituitary cell lines tested, none had specific receptors for somatostatin. Somatostatin was shown to inhibit prolactin and growth hormone production by CH4C1 cells. The dose-response characteristics for binding and the biological actions of somatostatin were essentially coincident. Furthermore, among several clonal pituitary cell strains tested, only those which had receptors for somatostatin showed a biological response to the hormone. We conclude that the characterized somatostatin receptor is necessary for the biological actions of somatostatin on GH4C1 cells.
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PMID:Characterization of functional receptors for somatostatin in rat pituitary cells in culture. 21 Jan 85

Somatostatin receptors in the rat pituitary gland were characterized by binding analysis with a radioiodinated high affinity somatostatin analogue, 125I-Tyr1[D-Trp8]somatostatin. Receptor binding of this derivative reached equilibrium at 30 min and was maintained at a plateau for at least 60 min. Two L-Trp8- labeled somatostatin analogues. 125I-Tyr1- and [125I-Tyr11]somatostatin, displayed less stable and lower specific uptake and higher nonspecific binding. In contrast to the rapid degradation of the L-Trp8 ligands during binding assay, 125I-Tyr1]D-Trp8]somatostatin retained more than 80% of its binding activity after 90 min of incubation with pituitary particles. Pituitary particles bound 125I-Tyr1]D-Tyr8]somatostatin with high affinity (Ka = 8.6 +/- 1.2 X 10(9) M-1) and capacity of 54.4 +/- 2.6 fmol/mg. These binding sites showed specificity for the native peptide and its active analogues, and other peptide hormones, including angiotensin II, thyrotropin-releasing hormone, vasopressin, oxytocin, substance P, and gonadotropin-releasing hormone, did not inhibit tracer binding. A good correlation was observed between the binding affinities of several somatostatin analogues and their potencies as inhibitors of growth hormone release in rat pituitary cells. These findings emphasize the physiological importance of the pituitary somatostatin receptor in mediating the inhibitory action of the peptide on growth hormone release. The use of Tyr1[d-Trp8]somatostatin as a labeled ligand permits accurate determinations of the binding affinity and concentration of receptors for somatostatin in the normal pituitary gland and provides a basis for further studies of somatostatin receptor regulation and receptor-mediated cellular effects of the tetradecapeptide.
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PMID:Pituitary somatostatin receptors. Characterization by binding with a nondegradable peptide analogue. 612 Jan 62

1. Somatostatin produces a voltage-dependent inhibition of N-type Ca2+ current in chick sympathetic neurons. Pretreatment of chick sympathetic ganglion neurons with protein kinase C (PKC) activators has no effect on calcium current (ICa) but reduces the inhibition of ICa by somatostatin. 2. The effects of the alkaloid PKC activator (-)-indolactam V were indistinguishable from those of 4 beta-phorbol-12-myristate-13-acetate (4 beta-PMA). The inactive isomers (+)-indolactam V and 4 alpha-PMA did not alter the modulation of ICa by somatostatin. 3. Modulation of ICa by somatostatin desensitizes, with a time for half desensitization of approximately 3 min. PKC activation mimics the normal desensitization process in that responses to 30 nM somatostatin are inhibited to a greater extent than are responses to 1 microM somatostatin. 4. PKC appears to act at the level of the somatostatin receptor or receptor-G protein interaction because PKC activation does not alter Ca2+ current inhibition in response to a nonhydrolyzable analog of GTP, GTP-gamma-S, which directly activates G proteins. 5. The specific PKC inhibitor calphostin C largely reverses the effects of phorbol esters, but does not slow the normal rate of desensitization of somatostatin responses. This indicates that PKC is not involved in the homologous desensitization of the somatostatin receptor. 6. Neither substance P, which activates PKC in these cells, nor arachidonic acid, another PKC activator, altered the action of somatostatin on ICa.
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PMID:Protein kinase C blocks somatostatin-induced modulation of calcium current in chick sympathetic neurons. 750 59

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.
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PMID:Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. 840 61

Due to the increased costs of medical care, a cost-benefit analysis is needed when trying for the 'ultimate' biochemical diagnosis of gastro-enteropancreatic (GEP) tumours. The glycoprotein chromogranin family has proved useful in screening for neuroendocrine tumours. In patients with midgut carcinoid tumours, chromogranin A is more sensitive than urinary 5-hydroxyindoleacetic acid but by combining these two biochemical markers most GEP tumours can be diagnosed. Chromogranin A is also a prognostic marker for survival in patients with midgut carcinoid tumours. Pancreastatin constitutes a part of the chromogranin A molecule and is a less sensitive general screening marker for neuroendocrine gut and pancreatic tumours, but levels, in combination with chromogranin A, might give some insight into tumour biology. Specific markers such as gastrin, glucagon, vasoactive intestinal peptide, insulin, neuropeptide K and substance P should be used to further characterise hormone production in neuroendocrine tumours. However, in some patients, confirmation of diagnosis requires provocation tests, such as the secretin or meal provocation tests. Staging information can be obtained by new investigations such as intra-operative or endoscopic ultrasound, octreoscan, and positron emission tomography. We combine the biochemical characterisation of neuroendocrine tumours with studies of growth factors/receptors, adhesion molecules, proliferation markers, somatostatin receptor content, induction of the enzymes p68 kinase and 2'5'-A-synthetase, and apoptosis, to establish a sound rationale for therapeutic decisions, enabling every patient to receive individualised treatment.
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PMID:The ultimate biochemical diagnosis of gastro-enteropancreatic tumours. 881 68

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for regulatory peptides such as somatostatin, substance P, vasoactive intestinal peptides, and cholecystokinin can be overexpressed in several human diseases, in particular in neoplasms, and represent therefore new molecular targets for cancer diagnosis and therapy. The availability of suitable regulatory peptide radioligands, which can be labeled with radioactive iodine or indium, makes peptide receptor scintigraphy a particularly useful new in vivo diagnostic tool, as seen with the example of somatostatin receptor scintigraphy (Octreoscan). The present article reviews the current in vitro data on regulatory peptide receptor expression in normal and diseased tissues, which represent the basis for the in vivo application of these molecules in nuclear medicine.
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PMID:Regulatory peptide receptors as molecular targets for cancer diagnosis and therapy. 920 45

Neuroendocrine gut and pancreatic tumors are known to contain and secret different peptide hormones and amines. During the last two decades, many radioimmunoassays and Elizas have been developed to analyze these substances in blood and urine, which has enabled clinicians to improve the diagnosis and monitoring of patients with various neuroendocrine tumors. Due to cost constraints in medical care, it is important to try to define the most useful biochemical markers from the clinical point of view. The glycoprotein chromogranin A has been shown to be a useful marker for diagnosing various neuroendocrine tumors, both by histopathology and circulating tumor markers. In patients with demonstrable endocrine tumors, about 90 percent of the patients present high circulating levels of chromogranin A. A hundred-fold increase of plasma chromogranin is seen in patients with midgut carcinoid tumors and liver metastases. The plasma levels of chromogranin A reflect the tumor mass and can be used for monitoring the patient during treatment and follow-up, although the day-to-day variation might be 30-40 percent. High circulating levels of the chromogranin A might be an indicator of bad prognosis in patients with malignant carcinoid tumors. Besides analyzing plasma chromogranin A, specific analyses such as urinary 5-HIAA in midgut carcinoid patients, serum gastrin in patients with Zollinger-Ellison syndrome and insulin/proinsulin in patients with hypoglycemia should be performed. In patients with small tumor masses or intermittent symptoms, provocative tests such as a meal stimulation test, secretin test or pentagastrin stimulation of tachykinin release can supplement the basal measurements of peptides and amines. To fully evaluate the growth potential in neuroendocrine tumors, traditional biochemical markers should be supplemented with indicators of growth proliferation (Ki-67, PCNA) and immunohistochemical staining for the adhesion molecule CD44 and the PDGF-alpha receptor. Finally, analysis of somatostatin receptor subtypes and induction of the enzymes 2-5A syntethase and PKR are of clinical value.
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PMID:Biochemical diagnosis of neuroendocrine GEP tumor. 982 77

Intrathecal administration of octreotide, a stable somatostatin analogue, provides pain relief in patients, and locally applied somatostatin inhibits firing of nociceptive dorsal horn neurons. In the present study, we have raised polyclonal antibodies that specifically detect the somatostatin receptor sst2A and used these antisera for immunocytochemical localization of the receptor protein in the rat spinal cord and dorsal root ganglia. In the superficial layers of the dorsal horn, sst2A-like immunoreactivity (Li) formed a dense network consisting of neuronal perikarya and dendrites which were often closely apposed by, but not co-contained within, somatostatin-14-immunoreactive nerve fibres and terminals. sst2A-Li was resistant to dorsal rhizotomy and did not colocalize with either substance P or calcitonin gene-related peptide suggesting that sst2A-Li was not located to primary afferents, but rather confined to second-order spinal neurons. The position of sst2A-Li perikarya and dendrites in the dorsal horn appeared to be similar to those containing mu-opioid receptor-Li; however, double labelling experiments revealed no instances of coexistence of these two receptors. sst2A-Li was also observed in the dorsal root ganglia predominantly targeted to the somatic plasmalemma of medium size neurons distinct from those expressing somatostatin-14 or delta-opioid receptors. Thus, the present results not only provide a morphological substrate for spinal octreotide analgesia but also show that somatostatin and opioids are poised to modulate nociceptive transmission by distinct anatomical systems.
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PMID:Immunocytochemical localization of somatostatin receptor sst2A in the rat spinal cord and dorsal root ganglia. 987 49

Human thymomas are rare tumours which usually develop in the chest. The diagnosis via guided biopsy, the evaluation of the extent of the tumour and its boundaries with adjacent organs, the choice of the appropriate therapeutic option, and the assessment of response to treatment are usually made with computed tomography (CT) alone or in combination with magnetic resonance imaging (MRI). More recently, radiopharmaceuticals and nuclear medicine procedures have been used increasingly in the imaging and functional characterization of benign and malignant thymic disorders. Two groups of radiopharmaceuticals have been used. The first includes several oncotropic tracers, such as 201Tl-chloride, 99mTc-sestamibi and 18F-fluorodeoxyglucose, which are significantly concentrated in thymic tumours. Their uptake correlates with tumour grades and cellularity. The second class includes two radioligands: [(111)In-DTPA-D-Phe1]-octreotide (DTPA, diethylenetriamine penta-acetic acid) and [(111)In-DTPA-Arg1]-substance P, which bind to specific receptors. [(111)In-DTPA-Arg1]-substance P binds to its receptors that are largely expressed in the thymus of patients with autoimmune diseases. [(111)In-DTPA-D-Phe1]-octreotide recognizes the somatostatin receptor subtype 2. In patients with active disease investigated in our institution [(111)In-DTPA-D-Phe1]-octreotide has been shown to concentrate in the majority of thymoma deposits. Conversely, it is not concentrated in adult patients with benign lymphofollicular thymic hyperplasia. This finding has had a significant impact on the management of patients with myasthenia gravis as it differentiates early-stage thymoma from benign hyperplasia, unlike CT and MRI, which often fail to distinguish between the two. In addition to its role in diagnostic imaging, somatostatin receptor scintigraphy also enables us to select patients with advanced or metastatic thymoma unresponsive to conventional therapies, who might benefit from a somatostatin analogue-based treatment, serving thus as a link between diagnosis and therapy. In this article, we discuss and analyse the results of functional imaging with different radiopharmaceuticals, primarily those that we have obtained with [(111)In-DTPA-D-Phe1]-octreotide.
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PMID:Functional imaging of thymic disorders. 1057 58

Somatostatin is part of an immunoregulatory circuit that helps limit interferon-gamma (IFNgamma) production at sites of chronic inflammation. In murine schistosomiasis. parasite eggs induce focal, chronic granulomatous inflammation in the liver and intestines. These granulomas produce somatostatin 1-14 and express somatostatin receptor subtype number 2 (SSTR2), which is the exclusive somatostatin receptor present in this inflammation. Granuloma and splenic macrophages as well as macrophage cell lines make somatostatin. There appears to be no other inflammatory cell source of the peptide. Various inflammatory mediators induce this expression, whereas substance P inhibits somatostatin production. Somatostatin can suppress IFN-gamma secretion from T cells via interaction with the SSTR2 receptor expressed on these cells. Other cells within the granuloma also display SSTR2. The effect of somatostatin on these other cell types remains unknown. The thymus of normal mice has a complete somatostatin regulatory circuit. The thymic epithelial and dendritic cells make somatostatin. Like the granulomas of murine schistosomiasis, the thymus expresses only SSTR2. Somatostatin likely has an important role in thymic T cell education and selection.
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PMID:The somatostatin immunoregulatory circuit present at sites of chronic inflammation. 1106 35


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