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)

Somatostatin and dopamine are two major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. However, the molecular basis for such interaction between the two systems is unclear. Here, we show that dopamine receptor D2R and somatostatin receptor SSTR5 interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity. Our results provide evidence that receptors from different G protein (heterotrimeric guanine nucleotide binding protein)-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new level of molecular crosstalk between related G protein-coupled receptor subfamilies.
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PMID:Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. 1076 37

In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which selectively binds to the SS subtype 2 receptor (sst(2); K(i) = 0.10 nM) and to the DA D2 receptor (D2DR; K(i) = 22.1 nM) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst(2) and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst(2) and D2DR mRNAs (0.8 +/- 0.2 and 4.7 +/- 0.7 copy/copy beta-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst(2) and D2DR analogs and by BIM-23A387 was similar. However, the mean EC(50) for GH suppression by BIM-23A387 (0.2 pM) was 50 times lower than that of the individual sst(2) and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst(2) antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 +/- 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.
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PMID:Demonstration of enhanced potency of a chimeric somatostatin-dopamine molecule, BIM-23A387, in suppressing growth hormone and prolactin secretion from human pituitary somatotroph adenoma cells. 1246 51

Somatostatin and dopamine receptors are well expressed and co-localized in several brain regions, suggesting the possibility of functional interactions. In the present study we used a combination of pharmacological, biochemical and photobleaching fluorescence resonance energy transfer (pbFRET) to determine the functional interactions between human somatostatin receptor 2 (hSSTR2) and human dopamine receptor 2 (hD2R) in both co-transfected CHO-K1 or HEK-293 cells as well as in cultured neuronal cells which express both the receptors endogenously. In monotransfected CHO-K1 or HEK-293 cells, D2R exists as a preformed dimer which is insensitive to agonist or antagonist treatment. In control CHO-K1 cells stably co-transfected with hD2R and hSSTR2, relatively low FRET efficiency and weak expression in co-immunoprecipitate from HEK-293 cells suggest the absence of preformed heterooligomers. However, upon treatment with selective ligands, hD2R and hSSTR2 exhibit heterodimerization. Agonist-induced heterodimerization was accompanied by increased affinity for dopamine and augmented hD2R signalling as well as prolonged hSSTR2 internalization. In contrast, cultured striatal neurons display constitutive heterodimerization between D2R and SSTR2, which were agonist-independent. However, heterodimerization in neurons was completely abolished in the presence of the D2R antagonist eticlopride. These findings suggest that hD2R and hSSTR2 operate as functional heterodimers modulated by ligands in situ, which may prove to be a useful model in designing new therapeutic drugs.
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PMID:Heterooligomerization of human dopamine receptor 2 and somatostatin receptor 2 Co-immunoprecipitation and fluorescence resonance energy transfer analysis. 1770 24

Dopamine and somatostatin are both involved in the negative control of normal pituitary cells. Dopamine subtype 2 receptor (D2DR) and somatostatin receptor (sst) agonists, mainly directed to sst2, are used in the treatment of pituitary adenomas. Nevertheless, a majority of corticotroph and gonadotroph adenomas and a third of somatotroph adenomas are still not sufficiently controlled by these treatments. D2DR and sst1, 2, 3 and 5 are present in most pituitary adenomas. These receptors may interact by heterodimerization as shown for sst1-sst5, sst5-D2DR, sst2-sst3 and sst2-D2DR suggesting possible additive effects. D2DR and sst2 agonist cotreatment showed limited additivity on GH secretion in acromegaly. Moreover, new chimeric compounds with sst2, D2DR and sst5 affinity have shown an increased control of secretion and/or proliferation of different types of pituitary adenomas in cell culture. Together with the multi-sst ligand drugs recently developed, these dopamine-somatostatin ligands represent a new opportunity in the combinatory treatment of pituitary adenomas.
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PMID:Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas. 1824 80

Somatostatin receptors (sst1-5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.
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PMID:Somatostatin-dopamine ligands in the treatment of pituitary adenomas. 1865 Dec 24

Somatostatin analogs and dopamine agonists are clinically used for medical therapy of functioning pituitary tumors, such as growth hormone- and prolactin-secreting tumors, however, their effects on ACTH-secreting tumors are controversial. This study was aimed to determine whether somatostatin receptor (SSTR) subtype (1-5) and dopamine receptor type 2 (D2R) are differentially expressed in pituitary tumors causing Cushing's disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumor (NFT). Tissue specimens were obtained from 35 pituitary tumors during transsphenoidal surgery. The steady-state mRNA levels of SSTR1-5 and D2R genes were determined by real-time reverse-transcription polymerase chain reaction. Both SSTR1 and 2 mRNA levels in SCA were greater than CD, while SSTR1 mRNA levels, but not SSTR2, in SCA were also greater than NFT. SSTR5 mRNA levels in CD were greater than SCA, but did not differ between NFT and SCA. SSTR4 mRNA expression was undetectable. D2R mRNA levels were markedly lower in CD and SCA than in NFT. The present study suggests that somatostatin analogs more selective for SSTR5 and for SSTR1 and/or 2may have the therapeutic potential for medical treatment of CD and SCA, respectively, whereas clinical application of dopamine agonists selective for D2R is very limited in either CD or SCA.
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PMID:Differential expression of somatostatin and dopamine receptor subtype genes in adrenocorticotropin (ACTH)-secreting pituitary tumors and silent corticotroph adenomas. 1931 29

The role of dopaminergic receptors in the control of GH release remains controversial. The dopamine receptor 2 (D2R) knockout mouse represents a useful model to study the participation of the D2R on growth and GHRH-GH regulation. These knockout mice have hyperprolactinemia and lactotrope hyperplasia, but unexpectedly, they are also growth retarded. In D2R knockout mice there is a significant decrease in somatotrope population, which is paralleled by decreased GH content and output from pituitary cells. The sensitivity of GHRH-induced GH and cAMP release is similar between genotypes, even though the response amplitude is lower in knockouts. We point to an involvement of D2R signaling at the hypothalamic level as dopamine did not release GH acting at the pituitary level, and both somatostatin and GHRH mRNA expression are altered in knockout mice. The similarity of the pituitary defect in the D2R knockout mouse to that of GHRH deficient models suggests a probable mechanism. Loss of dopamine signaling via hypothalamic D2Rs at a critical age may cause inadequate GHRH secretion subsequently leading to inappropriate somatotrope lineage development. Furthermore, GH pulsatility, which depends on a regulated temporal balance between GHRH and somatostatin output might be compromised in D2R knockout mice, leading to lower IGF-I, and growth retardation.
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PMID:Neurotransmitter modulation of the GHRH-GH axis. 2061 96

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein-coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.
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PMID:Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. 2063 7

Somatostatin and its synthetic analogs act through five specific somatostatin receptors (sstr1-5), found on the cell membrane of various tumors, including endocrine ones. Dopamine--a known neurotransmitter--acts through five membranous dopamine receptors (D1R-D5R) which have recently been found to be expressed in endocrine tumors. We evaluated the immunohistochemical expression of the sstrs and D2R in a large series of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A total of 22 (28.94%) well-differentiated NETs (WDNETs), 6 (7.89%) WDNETs of uncertain biology, 26 (34.21%) well-differentiated neuroendocrine carcinomas, and 22 (28.94%) poorly differentiated neuroendocrine carcinomas were studied. Overall, 76.31% of the tumors were positive for different types of sstrs with variable intensity of the membranous staining whereas 36.95% were positive for D2R alone. The sstr2A was the most frequently expressed, followed by sstr2B, sstr1, and sstr5. Co-expression of sstrs and D2R was seen in 88.23% of positive tumors. The high rates of sstr2A and sstr2B and in a lower extent of sstr5 expression are of great importance for more accurate imaging, staging and targeted therapy of the disease. The co-expression of sstrs and D2R in a significant number of the studied cases offers a potential therapeutic alternative for GEP-NETs.
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PMID:Somatostatin and dopamine receptor profile of gastroenteropancreatic neuroendocrine tumors: an immunohistochemical study. 2128 94

The presence and functional role of tumor stem cells in benign tumors, and in human pituitary adenomas in particular, is a debated issue that still lacks a definitive formal demonstration. Fifty-six surgical specimens of human pituitary adenomas were processed to establish tumor stem-like cultures by selection and expansion in stem cell-permissive medium or isolating CD133-expressing cells. Phenotypic and functional characterization of these cells was performed (1) ex vivo, by immunohistochemistry analysis on paraffin-embedded tissues; (2) in vitro, attesting marker expression, proliferation, self-renewal, differentiation, and drug sensitivity; and (3) in vivo, using a zebrafish model. Within pituitary adenomas, we identified rare cell populations expressing stem cell markers but not pituitary hormones; we isolated and expanded in vitro these cells, obtaining fibroblast-free, stem-like cultures from 38 pituitary adenoma samples. These cells grow as spheroids, express stem cell markers (Oct4, Sox2, CD133, and nestin), show sustained in vitro proliferation as compared to primary cultures of differentiated pituitary adenoma cells, and are able to differentiate in hormone-expressing pituitary cells. Besides, pituisphere cells, apparently not tumorigenic in mice, engrafted in zebrafish embryos, inducing pro-angiogenic and invasive responses. Finally, pituitary adenoma stem-like cells express regulatory pituitary receptors (D2R, SSTR2, and SSTR5), whose activation by a dopamine/somatostatin chimeric agonist exerts antiproliferative effects. In conclusion, we provide evidence that human pituitary adenomas contain a subpopulation fulfilling biological and phenotypical signatures of tumor stem cells that may represent novel therapeutic targets for therapy-resistant tumors.
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PMID:Phenotypical and Pharmacological Characterization of Stem-Like Cells in Human Pituitary Adenomas. 2751 54


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