Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of our study was to evaluate the effect of somatostatin (500 microgram/h intravenously) upon insulin, c-peptide, glucagon and plasma amino acids concentrations in patients with and without cirrhosis of the liver. The typical plasma amino acid pattern in cirrhosis is characterised by increased concentrations of the aromatic amino acids and decreased concentrations of the branched chain amino acids and of alanine and glycine. After administration of somatostatin insulin, c-peptide and glucagon concentrations decreased and those of the branched chain amino acids in both groups increased; in addition in patients with cirrhosis the plasma concentrations of threonine, serine, glycine, alanine, lysine, and arginine increased also. Infusion of somatostatin plus insulin in patients with cirrhosis succeeded in preventing the increase in the branched chain amino acid concentrations, while the infusion of somatostatin plus glucagon decreased threonine, serine, glycine, alinine, phenylalanine, tyrosine, lysine and arginine concentrations. It is therefore suggested that the effect of somatostatin on the plasma amino acids may be because of the reduction of insulin and glucagon concentrations; however, other effects of somatostatin cannot be excluded at present.
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PMID:Correction of altered plasma amino acid pattern in cirrhosis of the liver by somatostatin. 614 82

Modulation of voltage-dependent potassium currents can alter the shape and timing of action potentials, thereby altering neurotransmitter release. To examine the effect of a cAMP analog on potassium currents in metabolically intact cells, perforated-patch and cell-attached patch recordings were carried out using the GH4C1 pituitary cell line. A major component of voltage-dependent potassium current in these cells inactivates slowly, with a time constant of several seconds. Application of dibutyryl cAMP decreased this current at voltages positive to -10 mV and increased the rate of inactivation by approximately twofold. Single channel recordings revealed two channel types whose voltage dependence and kinetics of inactivation match those of the macroscopic current. One of these, the smaller conductance (7.5 pS) channel, was sensitive to the cAMP analog, which decreased the latency of the channel to enter a long-lasting inactivated state. Ensemble averages of the activity of this channel showed that, consistent with its effect on the macroscopic current, dibutyryl cAMP increased its rate of inactivation. Somatostatin, an agent that is known to activate a serine/threonine phosphatase in these cells, completely reversed the effect of dibutyryl cAMP on the channel, while the cyclic GMP analog, dibutyryl cyclic GMP was without effect. In contrast, the rate of inactivation of the larger conductance (approximately 19 pS) channel was not accelerated by dibutyryl cAMP. These studies indicate that different channel subtypes expressed in a single cell respond differently to elevations of cAMP, and suggest that the overall response of potassium currents to second messengers may be determined by the ratio of different channel subtypes.
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PMID:Modulation of the inactivation of voltage-dependent potassium channels by cAMP. 775 55

Effects of the stable somatostatin analogue RC-160 on cell proliferation, tyrosine phosphatase activity, and intracellular calcium concentration were investigated in CHO cells expressing the five somatostatin receptor subtypes SSTR1 to -5. Binding experiments were performed on crude membranes by using [125I-labeled Tyr11] somatostatin-14; RC-160 exhibited moderate-to-high affinities for SSTR2, -3, and -5 (IC50, 0.17, 0.1 and 21 nM, respectively) and low affinity for SSTR1 and -4 (IC50, 200 and 620 nM, respectively). Cell proliferation was induced in CHO cells by 10% (vol/vol) fetal calf serum, 1 microM insulin, or 0.1 microM cholecystokinin (CCK)-8; RC-160 inhibited serum-induced proliferation of CHO cells expressing SSTR2 and SSTR5 (EC50, 53 and 150 pM, respectively) but had no effect on growth of cells expressing SSTR1, -3, or -4. In SSTR2-expressing cells, orthovanadate suppressed the growth inhibitory effect of RC-160. This analogue inhibited insulin-induced proliferation and rapidly stimulated the activity of a tyrosine phosphatase in only this cellular clone. This latter effect was observed at doses of RC-160 (EC50, 4.6 pM) similar to those required to inhibit growth (EC50, 53 pM) and binding to the receptor (IC50, 170 pM), implicating tyrosine phosphatase as a transducer of the growth inhibition signal in SSTR2-expressing cells. In SSTR5-expressing cells, the phosphatase pathway was not involved in the inhibitory effect of RC-160 on cell growth, since this action was not influenced by tyrosine and serine/threonine phosphatase inhibitors. In addition, in SSTR5-expressing cells, RC-160 inhibited CCK-stimulated intracellular calcium mobilization at doses (EC50, 0.35 nM) similar to those necessary to inhibit somatostatin-14 binding (IC50, 21 nM) and CCK-induced cell proliferation (EC50, 1.1 nM). This suggests that the inositol phospholipid/calcium pathway could be involved in the antiproliferative effect of RC-160 mediated by SSTR5 in these cells. RC-160 had no effect on the basal or carbachol-stimulated calcium concentration in cells expressing SSTR1 to -4. Thus, we conclude that SSTR2 and SSTR5 bind RC-160 with high affinity and mediate the RC-160-induced inhibition of cell growth by distinct mechanisms.
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PMID:Inhibition of cell proliferation by the somatostatin analogue RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different mechanisms. 787 22

We investigated the mechanism by which a selective increase in arterial insulin can suppress hepatic glucose production in vivo. Isotopic (3-3H-glucose) and arteriovenous difference methods were used in overnight-fasted, conscious dogs. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon infusions) was used to control the endocrine pancreas. Equilibration (100 min) and basal (40 min) periods were followed by a 180-min test period. In control dogs (n = 5), basal insulin delivery was continued throughout the study. In the other two groups, peripheral insulin was selectively increased at the beginning of the test period by stopping the portal insulin infusion and infusing insulin peripherally at twice the basal portal rate. One group (INS + FAT; n = 6) received an infusion of 20% intralipid + heparin (0.5 U x kg(-1) x min(-1)) to clamp the nonesterified fatty acid (NEFA) levels during hyperinsulinemia; the other group (INS; n = 7) received only saline during the experimental period. In the INS group, a selective increase in peripheral insulin of 84 pmol/l was achieved (36 +/- 6 to 120 +/- 24 pmol/l, last 30 min) while portal insulin was unaltered (84 +/- 18 pmol/l). In the INS + FAT group, a similar increase in peripheral insulin was achieved (36 +/- 6 to 114 +/- 6 pmol/l, last 30 min); again, portal insulin was unaltered (96 +/- 12 pmol/l). In the control group, basal insulin did not change. Glucagon and glucose remained near basal values in all protocols. In the INS group, NEFA levels dropped from 700 +/- 90 (basal) to 230 +/- 65 micromol/l (last 30 min; P > 0.05), but in the INS + FAT group changed minimally (723 +/- 115 [basal] to 782 +/- 125 micromol/l [last 30 min]). In the INS group, net hepatic glucose output dropped by 6.7 micromol x kg(-1) x min(-1) (P < 0.05), whereas in the INS + FAT group it dropped by 3.9 micromol x kg(-1) x min(-1) (P < 0.05). When insulin levels were not increased (i.e., in the control group), net hepatic glucose output dropped 1.7 micromol x kg(-1) x min(-1) (P < 0.05). In all groups, the net hepatic glucose output data were confirmed by the tracer-determined glucose production data. In the INS group, net hepatic gluconeogenic substrate uptake (alanine, glutamine, glutamate, glycerol, glycine, lactate, threonine, and serine) fell slightly (10.4 +/- 1.3 [basal] to 7.2 +/- 1.3 micromol x kg(-1) x min(-1) [last 30 min]), whereas in the INS + FAT group it did not change (7.3 +/- 1.5 [basal] to 7.4 +/- 0.6 micromol x kg(-1) x min(-1) [last 30 min]), and in the control group it increased slightly (9.6 +/- 1.3 [basal] to 10.3 +/- 1.4 micromol x kg(-1) x min(-1) [last 30 min). These results indicate that peripheral insulin's ability to regulate hepatic glucose production is partially linked to its inhibition of lipolysis. When plasma NEFA levels were prevented from falling during a selective arterial hyperinsulinemia, approximately 55% of insulin's inhibition of net hepatic glucose output (NHGO) was eliminated. The fall in NEFA levels brings about a redirection of glycogenolytically derived carbon within the hepatocyte such that there is an increase in lactate efflux and a corresponding decrease in NHGO.
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PMID:The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. 900 Jun 93

Somatostatin (SRIF) was discovered as an inhibitor of GH secretion from pituitary somatotroph cells. SRIF analogs are very effective agents used to treat neuroendocrine tumors and are now being used with increasing frequency in clinical trials to treat more aggressive malignancies. However, the cellular components mediating SRIF signal transduction remain largely unknown. We have stably overexpressed the SRIF type 2 receptor (SST2) in GH4 rat somatomammotroph cells, establishing a physiologically relevant model system. In this model, the SRIF analog, BIM23014, inhibited forskolin-induced cAMP accumulation, protein kinase A activation, cAMP response element-binding protein phosphorylation, and Pit-1/GHF-1 promoter activation in an okadaic acid-insensitive manner. Pertussis toxin inhibited the effects of BIM23014, documenting that SST2 signaling was coupled to Gi. Moreover, the inhibitory effects of BIM23014 were reversed by overexpression of protein kinase A catalytic subunit, indicating that SRIF does not act via serine/threonine phosphatases, but, rather, by lowering protein kinase A activity. These data define the components of the SRIF/SST2 receptor signaling pathway and provide important mechanistic insights into how SRIF controls neuroendocrine tumors. As SRIF analogs are effective antitumor agents, and many other related compounds are in development, the knowledge gained here will further our understanding of their mechanism of action in other malignancies as well.
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PMID:Somatostatin acts by inhibiting the cyclic 3',5'-adenosine monophosphate (cAMP)/protein kinase A pathway, cAMP response element-binding protein (CREB) phosphorylation, and CREB transcription potency. 917 46

Neuropeptides affect food intake via peripheral and brainstem mechanisms, but their roles in mediating feeding via the cerebral cortex have received little attention. The anterior piriform cortex (APC) appears to play a critical role in neuroperception of deficiencies of essential amino acids (AA) and the anorectic response to such deficiencies. The neural circuitry underlying the role of this paleocortex in these events is not understood. We have shown that neurons containing neuropeptide Y (NPY) and somatostatin (SOM) are cytoarchitecturally in positions to relate synaptically to the neurons of the APC which may mediate responses to AA. Thus, we hypothesized that NPY and SOM administered intracortically to the APC would directly affect food intake in a threonine-imbalanced model. We determined that NPY at 1-1.5 nmol decreased intake of the AA-deficient diet for 3 h, with a cumulative effect that extended through 6 h. SOM had a dual effect; at 1 pmol it increased intake of the AA-deficient diet for 3 h; at 2 nmol, SOM decreased intake of the AA-deficient diet for over 9 h, with a cumulative effect that persisted through 12 h. In the first 3 h, intake of animals receiving 1 pmol of SOM differed significantly from those receiving 2 nmol. These results suggest that NPY and SOM affect the cortical circuitry responsible for recognition of deficiencies in nutritionally essential AA, and that the timing of the cortical responses to the peptides may be related to the time course of the anorectic responses.
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PMID:Neuropeptide Y and somatostatin in the anterior piriform cortex alter intake of amino acid-deficient diets. 953 41

A sequence motif of 20 amino acid residues within the C-terminal portion of the rat somatostatin receptor subtype 4 (SSTR4) has been shown to prevent rapid agonist-dependent receptor internalization in transfected human embryonic kidney (HEK) cells. Molecular dissection of this motif by biochemical ligand-binding assays revealed that the block was released by mutating a single residue (threonine 331) to an alanine. These data are in line with confocal microscopic analysis of cultured primary neurons microinjected with cDNA constructs encoding either SSTR4 or the mutant T331A. Immunocytochemical analysis showed that the mutant receptor, but not SSTR4, was internalized. However, internalized T331A was not recycled to the cell surface, suggesting that it lacks sequence elements that determine intracellular sorting after endocytosis. Neither wildtype SSTR nor the mutant T331A exhibited functional desensitization when assayed for their ability to inhibit adenylate cyclase. In agreement with this, the wt receptor and its mutant were not phosphorylated in response to agonist treatment. Lack of desensitization of SSTR4 has been electrophysiologically verified by coexpressing the receptor with a G-protein-gated, inwardly rectifying potassium channel in Xenopus oocytes. A strong somatostatin 14 (SST14)-activated inward potassium current was observed that was long-lasting and which decayed only slowly after washout of the agonist. This is in contrast to another somatostatin receptor subtype, SSTR3, which mediates rapidly desensitizing currents. Binding experiments on HEK cells transfected with either SSTR3 or 4 indicated that this difference is not attributable to slow dissociation of the agonist from the receptor, suggesting that SSTR4 mediates long-lasting signalling, a property which may be relevant for clinical therapy.
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PMID:Rat somatostatin receptor subtype 4 can be made sensitive to agonist-induced internalization by mutation of a single threonine (residue 331). 980 48

Phosphorylation of transcription factors fos/jun dimer activator protein (AP)-1 and nuclear factor-kappaB (NF-kappaB) plays a cardinal role in vascular smooth muscle cell (SMC) response to growth stimuli. Activity of protein tyrosine (PTP) and serine/threonine phosphatases (PP2A, B, and C) regulates in balance with the activity of protein kinases the level of transcription factor phosphorylation. Somatostatin analog octreotide stimulates phosphatase activity and inhibits cell growth. We examined in rats the activity of tissue phosphatases after arterial wall injury and treatment with octreotide and its effect on AP-1 and NF-kappaB phosphorylation and arterial response to injury. The activity of PTP did not change after balloon injury. Treatment of rats with PTP stimulator octreotide increased the PTP activity by 20% +/- 18% in uninjured arteries (p = 0.04 compared with control) and by 49% +/- 44% compared with injured untreated rats (p = 0.017). Treatment of rats with okadaic acid, a specific phosphatase inhibitor, prevented the octreotide-induced increase in PTP activity. PP2A activity of uninjured arteries was not affected significantly with treatment with octreotide (105% +/- 21%, p = 0.57 compared with control). After balloon injury PP2A activity was significantly reduced, 54% +/- 24% of control (p = 0.001). This reduction was prevented with treatment with octreotide, activity 88% +/- 25% of control. When rats were treated with octreotide and okadaic acid, the activity of PP2A in uninjured arteries was decreased to 65% +/- 12% of control (p = 0.03) and the injury-induced reduction was preserved, activity 54% +/- 8% of control (p = 0.001). There was no change in PP2B and C activity after balloon injury. Increased phosphatase activity with octreotide was associated with stabilization of the unphosphorylated form and reduction in nuclear binding of AP-1 and NF-kappaB and was associated with reduced SMC proliferation after balloon injury. Inhibition of increased phosphatase activity with okadaic acid was associated with increased nuclear binding of AP-1 and NF-kappaB. Increased nuclear binding of AP-1 and NF-kappaB after injury was associated with increased expression of fos, jun, and p105 subunit mRNA and restored the proliferative response of SMC after balloon injury. We conclude that the activity of PP2A is decreased after arterial balloon injury which leads to increased AP-1 and NF-kappaB phosphorylation and nuclear binding and is involved in regulation of SMC proliferation. Treatment with octreotide prevented the injury-induced reduction in PP2A activity and decreased transcription factor phosphorylation and SMC proliferation. Modification of phosphatase activity is a potential regulatory mechanism of arterial wall response to injury.
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PMID:Phosphatase activity in the arterial wall after balloon injury: effect of somatostatin analog octreotide. 1046 31

These studies were conducted to determine the effect of route of gluconeogenic amino acid delivery on the hepatic uptake of the amino acids. After a sampling period with no experimental intervention (basal period), conscious dogs deprived of food for 42 h received somatostatin, intraportal infusions of insulin (3-fold basal) and glucagon (basal), and a peripheral infusion of glucose to increase the hepatic glucose load 1.5-fold basal for 240 min. A mixture of alanine, glutamate, glutamine, glycine, serine and threonine was infused intraportally at 7.6 micromol. kg(-1). min(-1) (PorAA group, n = 6) or peripherally at 8.1 micromol. kg(-1). min(-1) (PerAA, n = 6), to match the hepatic load of gluconeogenic amino acids in PorAA. During the infusion period, there were no differences in PerAA and PorAA, respectively, with regard to arterial plasma insulin (144 +/- 18 and 162 +/- 18 pmol/L), glucagon (51 +/- 8 and 47 +/- 11 ng/L), hepatic glucose load (199.8 +/- 22.2 and 210.9 +/- 16.6 micromol. kg(-1). min(-1)), net hepatic glucose uptake (2.8 +/- 2.2 and 2.2 +/- 1.7 micromol. kg(-1). min(-1)), hepatic load of amino acids (68 +/- 14 and 62 +/- 7 micromol. kg(-1). min(-1)), or net hepatic glycogen synthesis (11.1 +/- 2.2 and 8.9 +/- 2.2 micromol. kg(-1). min(-1)). The net hepatic uptake of glutamine (2.1 +/- 0.4 vs. 0.8 +/- 0.3 micromol. kg(-1). min(-1)) and the net hepatic fractional extractions of glutamine (0.11 +/- 0.02 vs. 0.05 +/- 0.02) and serine (0.41 +/- 0.03 vs. 0.34 +/- 0.02) were greater in PorAA than in PerAA (P < 0.05). We speculate that one or more of the amino acids in the mixture causes enhancement of the net hepatic uptake and fractional extraction of glutamine, and perhaps other gluconeogenic amino acids, during intraportal amino acid delivery.
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PMID:Net hepatic gluconeogenic amino acid uptake in response to peripheral versus portal amino acid infusion in conscious dogs. 1057 53

In a continuation of our research efforts on the design and synthesis of novel peptidomimetic structures, we have synthesized a series of sandostatin amide analogs in which stereoisomers of threonine and beta-hydroxyvaline(beta-Hyv) are employed. The analogs D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Xaa6-Cys 7]-Xbb8-NH2 (Xaa = allo-Thr, D-allo-Thr, D-beta-Hyv, beta-Hyv, D-Thr, and Xbb = Thr or Xaa = Thr and Xbb = allo-Thr, D-allo-Thr, beta-Hyv, D-Thr) explore the effects on biological activity of stereochemical modifications and beta-methylation at positions 6 or 8. By these modifications, we examine the role of the two residues in binding to somatostatin receptors. We describe the synthesis and biological activity of these analogs. In combination with the results of the conformational analysis, this study provides new insights into the structural requirements for the binding affinity of somatostatin amide analogs to somatostatin receptors [Mattern et al., Conformational analyses of sandostatin analogs containing stereochemical changes in positions 6 or 8].
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PMID:Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8. 1077 65


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