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)

The biodistribution of several radiolabeled somatostatin (SRIF) analogs was determined in the rat. Newly developed analogs BIM-23190 and BIM-23197 attained higher plasma levels and much greater target tissue concentrations than the clinically used BIM-23014 analog. Highest tissue concentrations of BIM-23190 and BIM-23197 were found in adrenal, kidney, pituitary and pancreas, tissues that are known to be abundant in mRNA for the somatostatin subtype 2 receptor. BIM-23190 and BIM-23197 associated radioactivity in these tissues was prolonged compared with that of BIM-23014, especially in the SRIF-receptor-rich pituitary. BIM-23190 and BIM-23197 were more stable in vivo and much less subject to biliary excretion than BIM-23014. These properties account for the elevated plasma and target tissue concentrations of these new SRIF analogs. Based on higher plasma levels, greater distribution to target tissues and longer in vivo stability, BIM-23190 and BIM-23197 may prove to be superior to BIM-23014 for the treatment of acromegaly and some types of cancer.
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PMID:Novel somatostatin analogs for the treatment of acromegaly and cancer exhibit improved in vivo stability and distribution. 953 98

In the present study, we tested whether 17beta-estradiol (E2)-induced PRL sensitivity to somatostatin-14 (SRIF) involves selective up-regulation of discrete somatostatin receptor subtypes (ssts) in primary cultures of female rat pituitary cells. The efficacy of the endogenous peptide SRIF to inhibit GH and PRL secretion and cAMP accumulation was compared with those of octreotide (OCT), BIM-23052, BIM-23056, and BIM-23268, which have been reported to be relatively selective for rat sst2, sst3, and sst5. Experiments were performed in steroid-depleted media supplemented or not with 1 nM E2 for 96 h. SRIF, OCT, and BIM-23052 inhibited cAMP accumulation and GH release independently of E2. In contrast, all three agonists affected PRL release in E2-treated cultures only. Inhibition of cAMP accumulation by SRIF, OCT, and BIM-23052 was enhanced by exposure of cells to E2. The rank of potency of the agonists, OCT = SRIF > BIM-23052, was similar for GH and PRL inhibition. BIM-23268 was a weak agonist on GH, but not on PRL, secretion. BIM-23056 had no effect on the release of either hormone, but slightly inhibited cAMP formation in E2-treated cells. To verify whether SRIF receptor gene expression correlated with these observations, messenger RNA (mRNA) transcripts corresponding to the five ssts were measured by quantitative RT-PCR in the presence or absence of E2. Control cells expressed predominantly sst2 and sst3 transcripts; sst1 mRNA was present in moderate amounts, whereas sst4 and sst5 were only weakly expressed. E2 had a differential effect on distinct ssts; it increased mRNA concentrations corresponding to sst2 and sst3, and decreased that of sst1. These results indicate that sst2 and sst3 receptors are the major somatostatin receptors expressed in the female rat pituitary, and that both of them are positively regulated by estradiol. However, the capacity of lactotropes to respond to SRIF after exposure to E2 seems to depend more upon E2-induced up-regulation of the sst2 than of the sst3 receptor subtype.
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PMID:Effect of 17beta-estradiol on somatostatin receptor expression and inhibitory effects on growth hormone and prolactin release in rat pituitary cell cultures. 956 33

1. A high density of receptors for somatostatin (SRIF) exists in the anterior cingulate cortex but their function is unknown. Whole-cell patch clamp recordings were made from visualized deep layer pyramidal cells of the rat anterior cingulate cortex contained in isolated brain slices to investigate the putative effects of SRIF and to identify the receptor subtype(s) involved. 2. SRIF (1-1000 nM) produced a concentration-dependent outward current which was associated with an increased membrane conductance, was sensitive to Ba2+ (300 microM - 1 mM), and was absent in the presence of a maximal concentration of the GABA(B) receptor agonist, baclofen (100 microM). These observations suggest the outward current was carried by K+ ions. 3. SRIF analogues also elicited outward currents with a rank potency order of (EC50, nM): octreotide (1.8)>BIM-23027 (3.7)>SRIF (20)=L-362,855 (20). BIM-23056 was without agonist or antagonist activity. Responses to L-362,855 were unlike those to the other agonists since they were sustained for the duration of the application. 4. The sst2 receptor antagonist, L-Tyr8Cyanamid 154806 (1 microM), had no effect alone but partially reversed responses to submaximal concentrations of SRIF (100 nM, 44+/-6% reversal) and L-362,855 (100 nM, 70+/-6% reversal) and fully reversed the response to BIM-23027 (10 nM). In contrast, L-Tyr8Cyanamid 154806 did not antagonize the response to baclofen (10 microM). 5. We conclude that SRIF activates a K+ conductance in anterior cingulate pyramidal neurones via an action predominantly at sst2 receptors.
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PMID:Outward current produced by somatostatin (SRIF) in rat anterior cingulate pyramidal cells in vitro. 963 Mar 67

The effects of a potent specific gastrin-releasing peptide receptor antagonist, BIM 26226 ([D-F5 Phe6, D-Ala11] bombesin (6-13) OMe), and the long-acting somatostatin analogue, lanreotide (BIM 23014), on the growth of an acinar pancreatic adenocarcinoma growing in the rat or cultured in vitro were investigated. Lewis rats bearing a pancreatic carcinoma transplanted s.c. in the scapular region, were treated with gastrin-releasing peptide (30 microg/kg per day), BIM 26226 (30 and 100 microg/kg per day) and lanreotide (100 microg/kg per day) alone or in combination for 14 successive days. Chronic administration of BIM 26226 and lanreotide significantly inhibited the growth of pancreatic tumours stimulated or not by gastrin-releasing peptide (GRP), as shown by a reduction in tumour volume, protein, ribonucleic acid, amylase and chymotrypsin contents. This effect was more pronounced with 100 microg/kg per day BIM 26226 than with 30 microg/kg per day. However, BIM 26226 and lanreotide, given together, did not exert any additive effect on GRP-treated and -untreated tumours. In cell cultures, both BIM 26226 and lanreotide (10(-6) M) inhibited [3H]thymidine incorporation in tumour cells induced or not by GRP, but no increased effect was observed after combined treatment with both agents. Binding studies showed that BIM 26226 had a high affinity for GRP receptors in tumour cell membranes (IC50 = 6 nM). These results from in vivo and in vitro experiments suggest that BIM 26226 and lanreotide are able to reduce the growth of an experimental acinar pancreatic tumour. Thus, these agents represent interesting steps toward the development of new approaches for treatment of pancreatic carcinomas.
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PMID:Effect of the gastrin-releasing peptide antagonist BIM 26226 and lanreotide on an acinar pancreatic carcinoma. 965 Aug 51

Human somatostatin (somatotropin release inhibiting factor = SRIF) receptor subtypes sst2 and sst5 were stably expressed in Chinese hamster lung fibroblast (CCL39) cells. [125I][Tyr3]octreotide labelled with high affinity and in a saturable manner both sst2 (pKd = 9.89+/-0.02, Bmax = 210+/-10 fmol/mg, n = 3) and sst5 sites (pKd = 9.64+/-0.04, Bmax = 920+/-170 fmol/mg, n = 3). The pharmacological profile of sst2 sites established in CCL39 cells using SRIF and various peptide analogues was very similar to that described previously in CHO cells and in human cortex: SRIF14 = SRIF28 > or = seglitide > BIM 23014 = RC 160 > octreotide > CGP 23996 > or = L362,855 > BIM 23052 > L361,301 = cortistatin14 > BIM 23030 > BIM 23056 > cycloantagonist SA. However, peptides classically perceived as sst2 receptor selective (e.g., seglitide, octreotide, vapreotide) showed also high affinity for human sst5 receptors labelled with [125I][Tyr3]octreotide: SRIF28 > seglitide > SRIF14 > L361,301 = octreotide > cortistatin14 = BIM 23014 = BIM 23052 > L362,855 = RC160 > CGP 23996 > BIM 23056 > cycloantagonist SA > BIM 23030. Further radioligand binding studies were performed with [Leu8,D-Trp22,125I-Tyr25]SRIF28 ([125I]LTT-SRIF28) and [125I]CGP 23996. At sst2 receptors, Bmax values determined with [125I][Tyr3]octreotide, [125I]LTT-SRIF28 and [125I]CGP 23996 were in the same range (180-370 fmol/mg). 5'-Guanylyl-imidodiphosphate (GppNHp) displaced all three radioligands to the same extent (85%) and the pharmacological profiles were superimposable. By contrast, at sst5 receptors Bmax values were very different: [125I][Tyr3]octreotide (920 fmol/mg), [125I]CGP 23996 (3530 fmol/mg) and [125I]LTT-SRIF28 (6950 fmol/mg). GppNHp affected [125I][Tyr3]octreotide more than [125I]CGP 23996 binding, whereas [125I]LTT-SRIF28 was much less affected. In addition, the affinity values determined in competition experiments at sst5 receptors, varied markedly; whereas SRIF14, cortistatin14 and SRIF28 showed 2-, 4- and 8-fold differences in affinity at sst5 receptors labelled with [125I][Tyr3]octreotide and [125I]LTT-SRIF28 compounds such as RC160, L363,301, L362,855, octreotide or CGP 23996 showed between 42- and 123-fold lower affinity when sst5 sites were labelled with [125I]LTT-SRIF28. The present data suggest caution to be used when comparing affinity profiles determined in binding studies using different radioligands. In addition, the present results suggest that effects produced by octreotide and related short chain SRIF analogues on hormone release, modulation of tumour growth and central effects may be mediated by either sst2 and/or sst5 receptors.
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PMID:[125I][Tyr3]octreotide labels human somatostatin sst2 and sst5 receptors. 965 48

Somatostatin is a neuromodulator and neurotransmitter in the central nervous system. Administration of somatostatin to the spinal cord or brain areas involved in nociception has been shown to result in analgesia. Little information is available about the somatostatin receptor types which may be involved in mediating the neuromodulatory and analgesic effects of the peptide. To define the neuronal systems expressing the sst2(a) receptor in brain areas associated with analgesia, immunohistochemical co-localisation studies were carried out in the periaqueductal grey (PAG) and spinal cord using an antibody specific for the sst2(a) receptor. To further define sst2(a) receptor expressing neurones, sst2(a) receptor immunohistochemistry was combined with retrograde tracing using fluorogold. In the PAG, sst2(a) receptor expressing neurones were found to co-express calbindin D28k (36%), the glutamate transporter EAAC-1 (25%), and GABA transporter GAT-1 ( approximately 10%). A total of 65% of sst2(a) positive neurones projected to the thalamus. In the spinal cord, the sst2(a) receptor shows cellular co-localisation with EAAC-1 and GAT-1. Immunohistochemistry and receptor autoradiography using [125I]BIM 23027 after dorsal rhizotomy of the lumbar dorsal roots, L4 and L5, suggests that the somatostatin sst2(a) receptor is not present on primary afferent neurones. Dorsal hemisections of the mid thoracic cord did not alter the immunohistochemical signal for the somatostatin sst2(a) receptor, providing further evidence for an intrinsic localisation of the receptor protein in the dorsal horn of the spinal cord. These data show that the somatostatin sst2(a) receptor exists on morphologically and neurochemically heterogenous neurones and is closely associated with brain areas involved in analgesia and the modulation of nociception.
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PMID:Identification of somatostatin sst2(a) receptor expressing neurones in central regions involved in nociception. 966 64

Cold exposure increases TRH gene expression in hypothalamic and raphe nuclei and results in a vagal activation of gastric function. We investigated the role of medullary TRH receptors in cold (4-6 C, 90 min)-induced stimulation of gastric motor function in fasted conscious rats using intracisternal injections of TRH receptor (TRHr) antisense oligodeoxynucleotides (100 microg twice, -48 and -24 h). The gastric emptying of a methyl-cellulose solution was assessed by the phenol red method. TRH (0.1 microg) or the somatostatin subtype 5-preferring analog, BIM-23052 (1 microg), injected intracisternally increased basal gastric emptying by 34% and 47%, respectively. TRHr antisense, which had no effect on basal emptying, blocked TRH action but did not influence that of BIM-23052. Cold exposure increased gastric emptying by 64%, and the response was inhibited by vagotomy, atropine (0.1 mg/kg, i.p.), and TRHr antisense (intracisternally). Saline or mismatched oligodeoxynucleotides, injected intracisternally under similar conditions, did not alter the enhanced gastric emptying induced by cold or intracisternal injection of TRH or BIM-23052. These results indicate that TRH receptor activation in the brain stem mediates acute cold-induced vagal cholinergic stimulation of gastric transit, and that medullary TRH may play a role in the autonomic visceral responses to acute cold.
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PMID:Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats. 972 24

Somatostatin (somatotropin release-inhibiting factor, SRIF) interacts with G-protein coupled receptors (sst) designated sst1 through sst5. In PC12 and GC cells, SRIF binding sites were identified and mRNA receptor expression was evaluated. SRIF binding sites were expressed at a much lower density in PC12 (Kd = 21.2 +/- 3.9 nM; Bmax = 31 +/- 8 fmol/mg protein) than in GC cells (Kd = 6.4 +/- 1.6 nM; Bmax = 643 +/- 29 fmol/mg protein). sst3 receptor mRNA (81% of the total) was mainly expressed in PC12 cells, while sst1/2 receptor mRNAs were mostly expressed in GC cells (64 and 29%, respectively). In PC12 cells, adenylyl cyclase (AC) activity was unaffected by SRIF-14 (binding all SRIF receptors), octreotide (specific for sst2/3/5 receptors), BIM 23056 (binding sst3/5 receptors) or CH275 (specific for sst1 receptors), 1 microM each. In GC cells, SRIF-14 or octreotide, but not the two other peptides, significantly inhibited AC activity.
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PMID:Expression and coupling of somatostatin receptors in rat adrenal (PC12) and pituitary (GC) cell lines. 975 39

Somatostatin agonists are rapidly and efficiently internalized with the somatostatin sst2 receptor. The fate of internalized agonists and receptors is of critical importance because the rate of ligand recycling back to the cell surface can limit the amount of radioligand accumulated inside the cells, whereas receptor recycling might be of vital importance in providing the cell surface with dephosphorylated, resensitized receptors. Furthermore the accumulation of radioisotope-conjugated somatostatin agonists inside cancer cells resulting from receptor-mediated internalization has been used as a treatment for cancers that overexpress somatostatin receptors. In the present study, radio-iodinated agonists at the sst2 somatostatin receptor were employed to allow quantitative analysis of the fate of endocytosed agonist. After endocytosis, recycling back to the cell surface was the main pathway for both 125I-labelled somatostatin-14 (SRIF-14) and the more stable agonist 125I-labelled cyclo(N-Me-Ala-Tyr-d-Trp-Lys-Abu-Phe) (BIM-23027; Abu stands for aminobutyric acid), accounting for 75-85% of internalized ligand when re-endocytosis of radioligand was prevented. We have shown that there is a dynamic cycling of both somatostatin agonist ligands and receptors between the cell surface and internal compartments both during agonist treatment and after surface-bound agonist has been removed, unless steps are taken to prevent the re-activation of receptors by recycled agonist. Internalization leads to increased degradation of 125I-labelled SRIF-14 but not 125I-labelled BIM-23027. The concentration of recycled agonist accumulating in the extracellular medium was sufficient to re-activate the receptor, as measured both by the inhibition of forskolin-stimulated adenylate cyclase and the recovery of surface receptor number after internalization.
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PMID:Fates of endocytosed somatostatin sst2 receptors and associated agonists. 982 Aug 3

1. The operational characteristics of somatostatin (SRIF) sst4 receptors are poorly understood. In this study, we have characterized human recombinant sst4 receptors expressed in CHO cells (CHOsst4) by radioligand binding and microphysiometry. 2. Increasing concentrations SRIF or other SRIF receptor ligands inhibited specific [125I]-Tyr11-SRIF binding in CHOsst4 cell membranes with respective pIC50 values of SRIF (8.82), L-362855 (7.40), BIM-23027 (<5.5) and MK-678 (<5.5). 3. These ligands displayed agonist activity, producing concentration-dependent increases in rates of extracellular acidification (EAR) with pEC50 values of SRIF (9.6) and L-362855 (8.0), respectively. BIM-23027 and MK-678 were at least 1000 times weaker than SRIF. The SRIF maximum was about 40% of that observed with L-362855. 4. In the presence of SRIF (0.1-1 nM), concentration-effect curves to L-362855 were displaced to the right with a progressive reduction in the L-362855 maximum. 5. When cells were only exposed to a single maximally effective concentration of SRIF or L-362855, there was no difference in the magnitude of the agonist-induced increase in EAR. However, a second agonist challenge, 30 min later showed that responses to SRIF but not L-362855 were markedly desensitized. 6. When concentration-effect curves to SRIF and L-362855 were obtained by combining data from cells exposed to only a single agonist concentration, SRIF (pEC50 9.2) was approximately 20 times more potent than L-362855 (pEC50 8.0) but the maxima were the same. Responses to both SRIF and L-362855 were abolished by pertussis toxin. 7. SRIF and L-362855-induced increases in EAR were inhibited by N-ethyl isopropyl amiloride (10 microM) but were not modified by inhibitors of PKC (Go-6976), MAP kinase (PD-98059), tyrosine kinase (genistein) or tyrosine phosphatase (sodium orthovanadate). 8. The results suggest that SRIF-induced increases in EAR in CHOsst4 cells involved activation of the Na+/H+ antiporter and were mediated via Gi/Go G proteins. Responses to SRIF, but not L-362855, were subject to marked desensitization which may be a consequence of differential activation of receptor-effector coupling pathways.
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PMID:Differential agonist activity of somatostatin and L-362855 at human recombinant sst4 receptors. 983 22


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