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

Chronic rejection is the most common reason for late loss of a transplant. The molecular mechanism of chronic rejection is not known and there is no treatment for this disorder. The characteristic histological feature in chronic rejection is increased smooth muscle cell replication in the vascular wall, leading to allograft arteriosclerosis. In this study we demonstrate that nonimmunosuppressed rat aortic allografts undergoing chronic rejection synthesize increased quantities of several smooth muscle cell growth-promoting substances in the vascular wall including interleukin-1, eicosanoids, and several peptide growth factors. Administration of a stable somatostatin analog lanreotide, BIM 23014, strongly inhibits myocyte proliferation in the allograft in vivo. It has no inhibitory effect on the proliferation of smooth muscle cells in vitro. Concomitantly, the locally produced peptide growth factors, i.e., epidermal growth factor, insulin-like growth factor 1, and BB-isomer of platelet-derived growth factor, but not other mediators of inflammation, are significantly reduced. The results suggest that growth factors are the main effector molecules leading to myocyte proliferation in allograft arteriosclerosis and that allograft arteriosclerosis (chronic rejection) may be specifically inhibited by lanreotide administration.
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PMID:Somatostatin analog lanreotide inhibits myocyte replication and several growth factors in allograft arteriosclerosis. 837 Apr 76

The aim of this study was to examine the potencies of several recently identified selective somatostatin (SRIF)-receptor ligands as inhibitors of electrogenic ion transport in the rat distal colonic mucosa with the view to identifying the SRIF receptor type involved. Under basal conditions, cumulative administration of SRIF and SRIF28 decreased short circuit current (SCC), a measure of electrogenic ion transport, with EC50 values of 4 nM and 9 nM respectively. The peptidase inhibitors, phosphoramidon (1 microM) and amastatin (10 microM), has no effect on the potencies of either SRIF or SRIF28. The inhibitory action of SRIF on basal SCC was suppressed by piretanide and diphenylamine-2-carboxylate, compatible with the assumption that the Na+K+2Cl- co-transporter and Cl- channels, respectively, may be involved in this antisecretory action of SRIF. Tetrodotoxin (1 microM) had no effect on the antisecretory action of SRIF, suggesting that the process was not neuronally mediated. All of the SRIF analogues examined, with the exception of BIM-23056, maximally inhibited basal SCC to a similar extent as SRIF. Seglitide and octreotide were both more potent antisecretory agents than SRIF (respective EC50 values, 0.4 nM and 1.5 nM) suggesting that this effect was mediated by a receptor belonging to the SRIF1 receptor group. The most distinguishing feature of the rank order of agonist potencies was the high potency of the selective sst2 receptor ligand, BIM-23027 (EC50 value 0.32 nM), the weaker potency exhibited by the selective sst5 receptor ligand, L-362855 (EC50 value 21 nM), and the lack of agonist activity displayed by the selective sst3 receptor ligand, BIM-23056 (EC50 value > 1000 nM). This profile is comparable with that observed in binding studies on the recombinant sst2 receptor. Forskolin-stimulated secretion was suppressed by SRIF analogues with the rank order of agonist potencies BIM-23027 > SRIF > L-362855 >> BIM-23056 which resembled that exhibited under basal conditions. However, the absolute potencies of these agonists were lower (respective EC50 values 2 nM, 14 nM< 38 nM and > 1000 nM) whilst the magnitude of inhibition was about three fold greater. BIM-23027 and SRIF (both 30 nM) also inhibited carbachol-stimulated increases in basal SCC by 60-70%, while a similar concentration of L-362855 inhibited these responses by 11%. BIM-23056 (1 microM) had no effect on carbachol-simulated secretion. Radioligand binding studies on rat colonic mucosal membranes using [125I]-Tyr11-SRIF suggested heterogeneity of SRIF binding sites. Thus, SRIF and SRIF28 competed for binding (IC50 values, 0.32 and 0.63 nM, respectively) with Hill slopes less than unity; while seglitide and BIM-23027 both maximally displaced only 30-40% of specific binding with apparent high affinity (respective pIC50 values, 10.1 nM and 10.0). In conclusion, SRIF decreases basal as well as both cAMP and Ca(2+)-dependent Cl- secretion in rat colonic mucosa. The rank order of agonist potencies suggests that receptors resembling the recombinant sst2 receptor mediate inhibition of basal and forskolin-stimulated secretion. Radioligand binding studies suggest that BIM-23027 interacts with a sub-population of [125I]Tyr11-SRIF binding sites in rat colonic mucosal membranes which probably corresponds to the receptors mediating the antisecretory effects described here.
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PMID:Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa. 853 68

A range of somatostatin (SRIF) analogues have been used to characterize the SRIF receptor-mediating contraction of the human saphenous vein. SRIF produced concentration-dependent contractions with an EC50 value of approximately 20 nM. The peptidase inhibitors phosphoramidon and amastatin did not alter the potency of SRIF. The sst2 receptor-selective peptide BIM-23027 was approximately three times more potent than SRIF in contracting the vein, whereas the sst5 receptor-selective peptide L-362855 was approximately 50 times weaker. The sst3 receptor-selective peptide BIM-23056 did not contract the saphenous vein. Contractions to SRIF were not antagonised by the putative SRIF receptor blocker cyclo(7-aminoheptanoyl-Phe-D Trp-Lys-Thr[Bzl]) (CPP), phentolamine, or indomethacin. Decreasing the external calcium concentration reduced the maximum contraction to SRIF in a concentration-dependent manner without altering the EC50 value. Nifedipine and verapamil also markedly reduced the SRIF-induced contraction. SRIF and several SRIF analogues caused contraction of the human saphenous vein by what appeared to be a direct effect on the smooth muscle. Their relative potencies suggest that their effects were mediated by a somatostatin receptor that is like the recombinant sst2 receptor. The receptor transduction mechanism appears to involve activation of L-type calcium channels and entry of extracellular calcium.
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PMID:Somatostatin-induced contraction of human isolated saphenous vein involves sst2 receptor-mediated activation of L-type calcium channels. 863 86

1. The human recombinant somatostatin (SRIF) receptors, sst1 and sst2, have been stably expressed in mouse fibroblast (Ltk-) cells. Two stable clones, LSSR 1/20 and LSSR 11/13, expressing sst1 and sst2 receptors, respectively, have been used to characterize these receptor types using radioligand binding assays as well as measurements of changes in extracellular acidification rates using microphysiometry. 2. [125I]-[Tyr11]-SRIF bound to sst1 and sst2 receptors expressed in Ltk- cells with high affinity, Kd values being 1.52 nM, and 0.23 nM respectively. 3. In Ltk- cells expressing sst1 receptors, SRIF, SRIF-28, [D-Trp8]-SRIF and CGP 23996 all displaced [125I]-[Tyr11]-SRIF binding with high potency (IC50 values of 0.43 - 1.27 nM) whilst seglitide, BIM-23027, BIM-23056 and L-362855 were either weak inhibitors of binding or were ineffective. 4. In contrast MK-678 (seglitide) and BIM-23027 were the most potent inhibitors of [125I]-[Tyr11]-SRIF binding in Ltk- cells expressing sst2 receptors with IC50 values of 0.014 and 0.035 nM, respectively. 5. SRIF and a number of SRIF agonists, including seglitide and BIM-23027, caused concentration-dependent increases in extracellular acidification rates in Ltk- cells expressing sst2 receptors but not in Ltk- cells expressing sst1 receptors. The maximum increase in acidification rate produced by SRIF was 11.3 +/- 0.7% above baseline (0.1-0.28 pH unit min-1). The relative potencies of the SRIF agonists examined in causing increases in extracellular acidification rates in Ltk- cells expressing sst2 receptors correlated well with their relative potencies in inhibiting [125I]-[Tyr11] -SRIF binding (r = 0.94). 6. The increase in extracellular acidification produced by SRIF was markedly inhibited by pretreatment of cells with pertussis toxin (100 ng ml-1) indicating the involvement of pertussis toxin-sensitive G proteins. 7. SRIF (1 microM) had no effect on basal cyclic AMP levels in Ltk- cells expressing sst1 or sst2 receptors nor did it inhibit forskolin stimulated increases in cyclic AMP levels in either cell type. 8. The results from the present study describe the operational characteristics of human sst2 receptors expressed in Ltk- cells where receptor activation causes increases in extracellular acidification rates. This receptor is coupled to a pertussis toxin-sensitive G protein. In contrast, activation of sst1 receptors, at a similar transfection density, did not cause increases in extracellular acidification rates.
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PMID:Differences in the operational characteristics of the human recombinant somatostatin receptor types, sst1 and sst2, in mouse fibroblast (Ltk-) cells. 864 8

We investigated somatostatin receptors (SSTRs) in surgical specimens of prostate cancer and benign prostate hyperplasia (BPH), a normal immortalized epithelial cell line (PNT1), epithelial cancer cell lines, and stromal cells in short-term culture derived from normal and BPH biopsies. Cross-linking studies with 125I-Tyr11-SRIF-14 (125I-SRIF) and the SRIF analog 125I-BIM-23104 identified one major 57-kDa band both in surgical specimens and in epithelial and stromal cells cultures. In membrane-enriched fractions and whole stromal cells from a normal prostate and from one BPH, a single type of SSTR was characterized (Kd = 6.10(-9) and 10(-8) M, respectively, Bmax = 1.6 pmol per mg of proteins). mRNA for SSTR1 was detected in all epithelial and stromal cells tested except for PNT1, while SSTR2 mRNA was detected in one BPH stromal cell culture. BIM-23104 had no effect on the in vitro growth of the epithelial cells tested. Conversely, 10(-10) M BIM-23104 induced >50% growth inhibition of stromal cells after 6 days in culture. These results may have implications for therapeutic strategies using SRIF analogs in BPH and prostate cancer.
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PMID:Somatostatin receptors in prostate tissues and derived cell cultures, and the in vitro growth inhibitory effect of BIM-23014 analog. 867 27

The somatostatin receptor subtypes SSTR2 and SSTR5 mediate distinct endocrine and exocrine functions of somatostatin and may also be involved in mediating the neuromodulatory actions of somatostatin in the brain. To investigate whether these receptors couple to voltage-sensitive Ca2+ channels, SSTR2 and SSTR5 selective agonists were tested for their effects on AtT-20 cells using whole cell patch clamp techniques. The SSTR2 selective agonist MK 678 inhibited Ca2+ currents in AtT-20 cells. The effects of MK 678 were reversible and blocked by pertussis toxin pretreatment, suggesting that SSTR2 couples to the L-type Ca2+ channels via G proteins. Other SSTR2-selective agonists, including BIM 23027 and NC8-12, were able to inhibit the Ca2+ currents in these cells. The SSTR5 selective agonist BIM 23052 also inhibited the Ca2+ currents in these cells and this effect was reversible and blocked by pertussis toxin treatment. The ability of SSTR5 to mediate inhibition of the Ca2+ current was greatly attenuated by pretreatment with the SSTR5-selective agonist BIM 23052, whereas SSTR2-mediated inhibition of the Ca2+ current was not altered by pretreatment with the SSTR2-selective agonist MK 678. Thus, the SSTR2 and SSTR5 couplings to the Ca2+ current are differentially regulated. The peptide L362,855, which we previously have shown to have high affinity for the cloned SSTR5, had minimal effects on Ca2+ currents in AtT-20 cells at concentrations up to 100 nM and did not alter the ability of MK 678 to inhibit Ca2+ currents. However, it completely antagonized the effects of the SSTR5-selective agonist BIM 23052 on the Ca2+ currents. L362,855 is an antagonist/partial agonist at SSTR5 since it can reduce Ca2+ currents in these cells at concentrations above 100 nM. L362,855 is also an antagonist/partial agonist at the cloned rat SSTR5 expressed in CHO cells since it is able to block the inhibition of cAMP accumulation induced by somatostatin at concentrations below 100 nM but at higher concentrations can inhibit cAMP formation itself. Structural analysis of L362,855 reveals that only a single hydroxyl group at residue seven in the peptide is needed to convert the compound from an antagonist/partial agonist to a full agonist at SSTR5. These studies reveal that two different somatostatin receptor subtypes, SSTR2 and SSTR5, can mediate the inhibition of an L-type Ca2+ channel in AtT-20 cells by somatostatin. The receptor subtype responses can be distinguished by selective agonists and antagonists and are regulated differently by agonist pretreatment. The inhibition of Ca2+ influx into endocrine cells and neurons may be a major cellular mechanism by which somatostatin modulates hormone and neurotransmitter release. Our results reveal that at least two receptor subtypes can mediate this cellular response.
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PMID:Somatostatin receptor subtypes SSTR2 and SSTR5 couple negatively to an L-type Ca2+ current in the pituitary cell line AtT-20. 868 11

1. In order to characterize somatostatin (SRIF) receptor inhibiting spontaneous firing of rat locus coeruleus neurones, and their transduction mechanism(S), extracellular recordings were obtained from a pontine slice preparation of rat brain containing the locus coeruleus (LC). LC neurones were identified by electrophysiological and pharmacological properties; spontaneous firing (characteristically 0.5-5 Hz) was reversibly and concentration-dependently inhibited by exogenously applied noradrenaline. 2. Spontaneous firing of LC neurones was reversibly and concentration-dependently inhibited by SRIF and the N-terminally extended form, somatostatin-28 (SRIF-28), with EC50 values of 15.1 and 19.4 nM, respectively. The synthetic SRIF analogues (octreotide, MK-678, BIM-23027 and L-362,855) also caused concentration-dependent inhibition of LC neurone firing with a rank order of agonist potencies compatible with actions at a receptor resembling the recombinant sst2 receptor. The putative sst3 selective agonist, BIM-23056, was without agonist or antagonist effect. 3. Addition of 100 nM desipramine significantly increased the efficacy of exogenously applied noradrenaline (EC50 values, 2.96 and 0.13 microM, absence and presence of desipramine, respectively) but did not significantly affect SRIF-induced inhibition (EC50 values, 15.6 and 8.0 nM, respectively). Furthermore, application of phenoxybenzamine (3 microM) abolished responses to NA, but did not affect responses to SRIF (EC50 = 14.1 nM). 4. Application of the cyclic AMP analogue, 8-bromoadenosine-cyclic monophosphate (8-Br-cyclic AMP; 500 microM), significantly increased the spontaneous firing rate of all neurones tested (223 +/- 24% over basal rate). Concentration-effect curves for SRIF constructed in the absence and presence of 8-Br-cyclic AMP had similar threshold concentrations, maxima and EC50 values. 5. Incubation of pontine slices in a modified artificial CSF containing 500 ng ml-1 pertussis toxin (PTX) for 18 h prior to extracellular recording affected neither the spontaneous firing of LC neurones, nor the inhibitory responses to muscimol (EC50 2.2 and 1.2 microM, absence and presence of PTX). However, inhibitory responses to SRIF were markedly attenuated. 6. We conclude that the inhibitory actions of SRIF on spontaneous firing of LC neurones are mediated directly by activation of somatodendritic SRIF receptors, and not indirectly by release of noradrenaline. The SRIF receptors involved appear to couple via a pertussis toxin sensitive G-protein, and elicit their response by a mechanism apparently independent of inhibition of cyclic AMP formation. The agonist profile of several selective and novel SRIF analogues suggests the identity of this receptor to be similar to the recombinant sst2 receptor.
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PMID:Operational characteristics of somatostatin receptors mediating inhibitory actions on rat locus coeruleus neurones. 873 75

A variety of human neuroendocrine tumours express SSTR. The five recently cloned human SSTR subtypes have a distinct chromosomal localization and pharmacological profile, and a tissue-specific expression pattern which suggests a differential function of SSTR subtypes in different organ systems. Most tumours carrying SSTR may express multiple SSTR subtypes, while the SSTR2 subtype is most predominantly expressed. The somatostatin analogue, octreotide, binds with high affinity to the SSTR2 and SSTR5 subtype and with a low affinity to the SSTR3 subtype. This analogue does not bind to the SSTR1 and SSTR4 subtypes. No major differences in the binding characteristics have been found between octreotide and two other clinically used octapeptide SST-analogues, BIM-23014 and RC-160. Our preliminary data indicate that an absent hormonal response to octreotide in vitro also implies an absent response to BIM-23014 and RC-160. The expression of the SSTR2 subtype in human tumours is proposed to be related to a clinical beneficial effect of octreotide treatment, while the functional significance of the other SSTR subtypes is not clear at present. In addition it is unclear which subtype(s) is involved in the antimitotic actions of SST(-analogues). Further developments with regard to the oncological application of SST analogues await the identification of the SSTR subtype(s) mediating anti-proliferative effects, as well as the development of analogues which selectively activate this subtype(s). A good correlation has been found between the presence of SSTR2 subtype mRNA and binding of [125I-Tyr3]octreotide in human primary tumours. Therefore, SSTR scintigraphy of human primary tumours and their metastases presumably visualizes SSTR2-expressing tumours, although it is reasonable to assume that SSTR5, and to a lesser extent SSTR3, when expressed simultaneously with SSTR2, also contribute to the visualization of tumours.
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PMID:Somatostatin receptors and disease: role of receptor subtypes. 873 55

We have investigated the effects of somatostatin (SRIF) and the linear octapeptide BIM-23056 on changes in intracellular calcium ion concentration ([Ca2+]i) and on the formation of inositol-1,4,5-trisphosphate (Ins(1,4,5)P3) in CHO-K1 cells transfected with the human recombinant SRIF sst5 receptor. SRIF elicited concentration-dependent increases in [Ca2+]i, with a pEC50 of 7.02 +/- 0.06, while BIM-23056 (1 x 10(-7) M) behaved not as an agonist but as a potent, surmountable antagonist of these increases in [Ca2+]i. The SRIF concentration-effect curve for increases in [Ca2+]i was shifted rightward producing an estimated pKB for the antagonist of 8.0. BIM-23056 (1 x 10(-7) M) also significantly attenuated Ins(1,4,5)P3 increases due to SRIF, but had no effect on either basal or uridine 5'-triphosphate (UTP) (1 x 10(-4) M) stimulated increases in the levels of [Ca2+]i or Ins(1,4,5)P3.
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PMID:Potent antagonism by BIM-23056 at the human recombinant somatostatin sst5 receptor. 876 63

In the past few years, five different somatostatin (SRIF) receptor subtypes (sst1.5) have been identified, which form a distinct group in the superfamily of G-protein-coupled receptors. The naturally occurring somatostatins SRIF-28, SRIF-25, and SRIF-14 all reveal high-affinity binding for sst1.5. In contrast, short synthetic analogs that are in clinical use, such as SMS 201-995, RC-160, or BIM 23014, primarily interact with the sst2 subtype. Some SRIF analogs were previously reported to be selective for one SRIF receptor subtype, eg, the sst2 (MK 678), the sst3 (BIM 23056), or the sst5 (BIM 23052, L362-855) subtype. However, when we studied the binding affinities of these SRIF analogs for human (h) sst1.5 expressed in either CHO or COS-1 cells, we were unable to confirm these previously reported selectivities. The absence of sst antagonists is a major drawback for investigating the functional role of each sst subtype. We used site-directed mutagenesis to identify amino acids that determine ligand specificity for sst2. A single Ser305 to Phe mutation in TM VII increased the affinity of hsst1, for SMS 201-995 nearly 100-fold, and when Gln291 was also exchanged to Asn in TM VII of hsst1, almost full sst2-like binding of SMS 201-995 was obtained. These data may aid in the design and synthesis of new selective type sst ligands. We have identified the expression of sst subtypes in nonclassical SRIF target tissue such as the lung. The pKi values for SRIF and various SRIF analogs in rat lung tissue preparations were in close correlation with those obtained for CHO cells expressing the sst4 subtype. Furthermore, reverse transcriptase polymerase chain reaction (RT-PCR) experiments revealed the predominant expression of mRNA specific for sst4 in mouse, rat, and human lung tissue, confirmed by autoradiographies of rat lung. No specific binding for [125I]Tyr3-SMS 201-995 was detected, since SMS 201-995 has low affinity for sst4. In contrast, specific binding of [125I]SRIF-28 to rat lung sections was demonstrated, which could be displaced by unlabelled SRIF-14 and SRIF-28, indicating specific, high affinity binding of this radioligand to sst4 receptors.
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PMID:Binding properties of somatostatin receptor subtypes. 876 72


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