UNIPROT:P61278 - FACTA Search

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent accumulation of biogenic amine inside the secretory granules of endocrine cells and neurons and was demonstrated in the histamine-producing enterochromaffin-like (ECL) cells of the stomach. In the present investigation, VMAT2 immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated (neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2 parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2 immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12 of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach (differentiated cells only). No VMAT2 immunoreactivity was observed in five gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths, and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2 immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell tumors, separating them from all other endocrine tumors arising in the gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of which proved essentially negative.
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PMID:Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors. 1078 79

Adenylyl cyclase, the enzyme that converts ATP to cAMP, is regulated by its stimulatory and inhibitory GTP-binding proteins, G(s) and G(i), respectively. Recently, we demonstrated that besides catalyzing the synthesis of cAMP, type V adenylyl cyclase (ACV) can act as a GTPase-activating protein for Galpha(s) and also enhance the ability of activated receptors to stimulate GTP-GDP exchange on heterotrimeric G(s) (Scholich, K., Mullenix, J. B., Wittpoth, C., Poppleton, H. M., Pierre, S. C., Lindorfer, M. A., Garrison, J. C., and Patel, T. B. (1999) Science 283, 1328-1331). This latter action of ACV would facilitate the rapid onset of signaling via G(s). Because the C1 region of ACV interacts with the inhibitory GTP-binding protein Galpha(i), we investigated whether the receptor-mediated activation of heterotrimeric G(i) was also regulated by ACV and its subdomains. Our data show that ACV and its C1 domain increased the ability of a muscarinic receptor mimetic peptide (MIII-4) to enhance activation of heterotrimeric G(i) such that the amount of peptide required to stimulate G(i) in steady-state GTPase activity assays was 3-4 orders of magnitude less than without the C1 domain. Additionally, the MIII-4-mediated binding of guanosine 5'-(gamma-thio)triphosphate (GTPgammaS) to G(i) was also markedly increased in the presence of ACV or its C1 domain. In contrast, the C2 domain of ACV was not able to alter either the GTPase activity or the GTPgammaS binding to G(i) in the presence of MIII-4. Furthermore, in adenylyl cyclase assays employing S49 cyc(-) cell membranes, the C1 (but not the C2) domain of ACV enhanced the ability of peptide MIII-4 as well as endogenous somatostatin receptors to activate endogenous G(i) and to inhibit adenylyl cyclase activity. These data demonstrate that adenylyl cyclase and its C1 domain facilitate receptor-mediated activation of G(i).
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PMID:Adenylyl cyclase regulates signal onset via the inhibitory GTP-binding protein, Gi. 1085 6

The effects of native somatostatin-14 (SS-14) and of its two analogues, octreotide and CH-275, on the activity of tyrosine kinases (TK) in two rodent tumors (rat pituitary tumor and murine colonic cancer) were studied in vitro. The activity of TK was measured in tissue homogenates using gamma[(32)P]ATP as the donor of the phosphoryl group and poly(Glu(80), Tyr(20)) as a substrate. It was found that native SS-14 inhibited TK activity in both investigated tumors. Octreotide, which acts preferentially via somatostatin receptor subtype 2 (SSTR2), was very effective in inhibiting TK activity in the rat pituitary tumor, but it is a rather weak inhibitor of TK activity in murine colonic cancer. CH-275, a selective ligand of the SSTR1 subtype of SS receptors, suppressed TK activity in the pituitary tumor but was ineffective in the colonic cancer. It is hypothesized that the effect of neuropeptide somatostatin (SS-14) on murine colonic cancer is exerted via the subtype of receptor which does not interact with CH-275 and has no or low affinity for octreotide (SSTR 4, 3 or 5?).
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PMID:Effects of somatostatin and its analogues on tyrosine kinase activity in rodent tumors. 1096 60

There is controversy as to whether somatostatin sst(4) receptors internalize. In this study, CHO-K1 cells expressing human sst(4) receptor (CHOsst(4) cells) cells internalized [(125)I]-[(11)Tyr]-SRIF in a time-dependent manner, reaching a steady state at 60 min (1.4+/-0.1x10(4) molecules internalized per cell). Internalization was blocked by hypertonic sucrose (0.5 M), ATP depletion or by decreasing the temperature to 4 degrees C. Internalization of [(125)I]-[(11)Tyr]-SRIF was also inhibited (pIC(50) values) by increasing concentrations of SRIF (7.74), L-362855 (6.27) and NNC-296100 (6.50) with pIC(50) values approximately 10 fold lower than those obtained for inhibition of [(125)I]-[(11)Tyr]-SRIF binding to membrane homogenates. Internalized ligand recycled rapidly to the extracellular media (t(1/2) 3.9+/-0.7 min) with only 6.8+/-0.6% of internalized radioactivity remaining in the cell after 45 min. Confocal microscopy of permeabilized, HA-epitope tagged CHOsst(4) cells labelled with a Cy-3 conjugated antibody revealed little internal immunostaining after SRIF (1 microM) treatment, consistent with the small proportion of receptors (3.5%) estimated to be internalized by radioimmunoassay. In summary, CHOsst(4) cells internalized [(125)I]-[(11)Tyr]-SRIF in a clathrin- and ATP-dependent manner with subsequent rapid recycling to the extracellular medium. Rapid receptor recycling and the consequent low proportion of receptors internalized at any one time may explain the inability to visualize internalized receptors by confocal microscopy. It seems unlikely therefore that the marked receptor desensitization observed in CHOsst(4) cells following SRIF treatment can be accounted for by a decrease in cell surface receptor expression.
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PMID:Ligand internalization and recycling by human recombinant somatostatin type 4 (h sst(4)) receptors expressed in CHO-K1 cells. 1122 41

The subcommissural organ (SCO) of mammals is innervated by several neuropeptide and neurotransmitter systems. So far, substance P (SP), oxytocin (OXT), vasopressin (VP), somatostatin (SOM), thyrotropin-releasing factor (TRF), and angiotensin II (ANGII) were identified in neuropeptidergic input systems, and serotonin (5HT), gamma-amino butyric acid (GABA), noradrenaline (NA), dopamine (DA), and acetylcholine (Ach) were neurotransmitters observed in systems afferent to the SCO. In the present report, based on literature data and our own investigations, we describe the occurrence of peptide and transmitter receptors in the SCO by means of autoradiographic and biochemical studies. Further, we summarize aspects of the signal transduction cascades possibly linked to different receptor types of the SCO; these studies included the use of calcium imaging (FURA-2 technique), ELISA technique, and immunocytochemistry. Receptors were identified for adenosine, angiotensin II, imidazoline, glucocorticoids, mineralocorticoids, NA, and embryonic brain kinase. The studies on intracellular signal-transduction indicated receptors for tachykinins and for ATP. In SCO cells, Ca(++) and c-AMP were identified to act as second messengers. As important transcription factor, cAMP-/Ca(++)-response element binding protein (CREB) was observed. Ach and NA did not show a significant effect on the subcommissural signal transduction.
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PMID:Presence and functional significance of neuropeptide and neurotransmitter receptors in subcommissural organ cells. 1124 63

We characterized morphologic and secretory properties of porcine pancreatic endocrine cells in primary culture obtained by autolytic preparation without any exogenous proteolytic enzymes. The endocrine cells exhibited a neuron-like shape, and insulin granules were accumulated at the terminal of the processes. Thus derived endocrine cells survived in culture medium containing nicotinamide and remained sensitive to glucose for at least 6 weeks after preparations. The cells responded well to physiologic concentrations of glucose, and high K+ depolarization and the antidiabetic sulfonylureas, tolbutamide, and glibenclamide also elicited the release. With high glucose, insulin release was markedly potentiated by forskolin, glucagon, glucagon-like peptide-1, and arginine and inhibited by somatostatin, the Ca2+ channel blocker nitrendipine, and the ATP-sensitive K+ channel opener diazoxide. Epinephrine had dual effects on the release by glucose; enhanced within a low nanomolar range and inhibited at 1 micromol/L. However, the cells were unresponsive to leucine. Such secretory sensitivities to nutrients, hormones, and pharmacologic agents, and long survival rate (as long as 5-6 weeks) of these cells suggest to us therefore that derived endocrine cells may be useful for xenotransplantation of pancreatic beta cells for treatment of insulin-dependent diabetes mellitus.
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PMID:Characterization of secretory and morphologic properties of primary cultured endocrine cells from porcine pancreata. 1124 67

Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1 (GenBank accession number L78207) is the first report of familial HI among nonconsanguineous Caucasians identified in the U.K. Using patch-clamp methodologies, we have shown that this mutation is associated with both a decrease in the number of operational ATP-sensitive K+ channels (KATP channels) in beta-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca2+- and voltage-gated K+ channels or delayed rectifier K+ channels. Intact HI beta-cells were spontaneously electrically active and generating Ca2+ action currents that were largely insensitive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intracellular free calcium ion concentration ([Ca2+]i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI beta-cells revealed that there were no defects in Ca2+-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca2+]i signaling, glucose readily promoted insulin release. Glucose was also found to augment the actions of protein kinase C- and protein kinase A-dependent agonists in the absence of extracellular Ca2+. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time KATP channel-independent pathways of regulated insulin secretion in diseased human beta-cells.
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PMID:Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways. 1127 44

Western blotting revealed the presence of five somatostatin receptor types, sst1, sst2, sst3, sst4 and sst5, in the mouse pancreatic -cell line MIN-6. In MIN-6 cells, glucose-induced electrical activity was potently (pEC50 = 12.7) and irreversibly reduced by somatostatin (SRIF-14); this was associated with hyperpolarization of the membrane potential (pEC50 = 11.2) and a decrease in the input resistance (pEC50 = 12.7). The effects of SRIF-14 were mimicked by 100 nM L-362,855 (a partial agonist at sst5 receptors), but not BIM-23027 or NNC-26,9100 (selective agonists at sst2 and sst4 receptors, respectively). CH-275 at 100 nM (a selective agonist at sst1 receptors) partially inhibited electrical activity but without membrane potential hyperpolarization. One hundred nanomolar SRIF-28 activated an inwardly rectifying K+ current (ISRIF) ISRIF was activated neither by 1 M BIM-23056 nor CYN-154806 (antagonists at sst5 and sst2 receptors, respectively). The activation of ISRIF by 100 nM SRIF-28 was, however, inhibited 93 % by BIM-23056; CYN-154806 had no effect. Both 100 nM glibenclamide and 200 M tolbutamide, blockers of the -cell ATP-sensitive K+ channel (K-ATP), reduced ISRIF by ~44 %, whereas 1 mM Ba2+ abolished ISRIF. In cell-attached patches, 100 nM SRIF-14 activated two types of single-channel currents whose properties were consistent with those of K-ATP and GIRK channels. In conclusion, somatostatin can inhibit glucose-induced electrical activity in MIN-6 cells by the combined activation of K-ATP and GIRK channels. Studies with selective agonists and antagonists are consistent with this effect being mediated by the sst5 receptor.
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PMID:Somatostatin activates two types of inwardly rectifying K+ channels in MIN-6 cells. 1128 30

Somatostatin hyperpolarized rat pancreatic alpha-cells and inhibited spontaneous electrical activity by activating a low-conductance K+ channel (0.9 pS with physiological ionic gradients). This channel was insensitive to tolbutamide (a blocker of ATP-sensitive K+ channels) and apamin (an inhibitor of small-conductance Ca(2+)-activated K+ channels). Channel activation was prevented by pre-treating the cells with pertussis toxin, indicating the involvement of G-proteins. A direct interaction between an inhibitory G-protein and the somatostatin-activated K+ channel is suggested by the finding that intracellular application of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma-S) and the G beta gamma subunit of G-proteins resulted in a transient stimulation of the current. Activation of the K+ current by somatostatin was inhibited by intracellular dialysis with specific antibodies to Gi1/2 and was not seen in cells treated with antisense oligonucleotides against G-proteins of the subtype Gi2. We conclude that somatostatin suppresses alpha-cell electrical activity by a Gi2-protein-dependent mechanism, which culminates in the activation of a sulphonylurea- and apamin-insensitive low-conductance K+ channel.
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PMID:Gi2 proteins couple somatostatin receptors to low-conductance K+ channels in rat pancreatic alpha-cells. 1137 64

1. Measurements of cell capacitance were used to investigate the molecular mechanisms by which somatostatin inhibits Ca(2+)-induced exocytosis in single rat glucagon-secreting pancreatic alpha-cells. 2. Somatostatin decreased the exocytotic responses elicited by voltage-clamp depolarisations by 80 % in the presence of cyclic AMP-elevating agents such as isoprenaline and forskolin. Inhibition was time dependent and half-maximal within 22 s. 3. The inhibitory action of somatostatin was concentration dependent with an IC(50) of 68 nM and prevented by pretreatment of the cells with pertussis toxin. The latter effect was mimicked by intracellular dialysis with specific antibodies to G(i1/2) and by antisense oligonucleotides against G proteins of the subtype G(i2). 4. Somatostatin lacked inhibitory action when applied in the absence of forskolin or in the presence of the L-type Ca(2+) channel blocker nifedipine. The size of the omega-conotoxin-sensitive and forskolin-independent component of exocytosis was limited to 60 fF. By contrast, somatostatin abolished L-type Ca(2+) channel-dependent exocytosis in alpha-cells exposed to forskolin. The magnitude of the latter pool amounted to 230 fF. 5. The inhibitory effect of somatostatin on exocytosis was mediated by activation of the serine/threonine protein phosphatase calcineurin and was prevented by pretreatment with cyclosporin A and deltamethrin or intracellularly applied calcineurin autoinhibitory peptide. Experiments using the stable ATP analogue AMP-PCP indicate that somatostatin acts by depriming of granules. 6. We propose that somatostatin receptors associate with L-type Ca(2+) channels and couple to G(i2) proteins leading to a localised activation of calcineurin and depriming of secretory granules situated close to the L-type Ca(2+) channels.
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PMID:Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules. 1153 41

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