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)

Shifts in the distribution of the monovalent cations Na+ and K+ between the extra- and intracellular space seem to be important for the secretory response of the beta-cell. An attempt was therefore made to study the enzyme responsible for monovalent cation transport, the (NaK)-activated ATPase. In the presence of NaN3 as inhibitor of the mitochondrial Mg-ATPase, a NaK-ATPase with a specific activity of 72 mU X mg protein-1 could be demonstrated in crude membrane preparations of rat pancreatic islets. The enzyme, which was inactive in the absence of Mg++, needed both Na+ and K+ for activation and was inhibited by ouabain and PCMB. The main part of the NaK-ATPase was localized in the microsomal fraction. Glucose, sulphonylureas, somatostatin and diazoxide were without effect on NaK-ATPase.
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PMID:NaK-ATPase in rat pancreatic islets. 14 87

It is now well established that insulin biosynthesis proceeds through a precursor molecule, proinsulin. This single polypeptide chain form has been identified as a ribosomal product in the microsomal fraction from islet tissues. The newly synthesized peptide chain, after folding and thiol oxidation, is transferred to the Golgi apparatus where it begins to undergo proteolytic processing to insulin and packaging into secretory granules. The secretion from the cells of significant amounts of newly synthesized material by exocytosis begins only one hour or more after biosynthesis and this process is regulated by several factors, including glucose. Foci of current attention discussed in this paper include (1) the possible existence of larger precursor forms than proinsulin, especially short-lived biosynthetic transients with extended NH2-termini analogous to the recently described immunoglobulin L chain and proparathyroid hormone precursors; (2) the large-scale production of insulin by chemical or genetic engineering approaches; (3) isolation of beta-cell plasma membranes; (4) regulatory mechanisms for the biosynthesis and secretion of insulin, the possible role of mRNA modification in this process, and effects of somatostatin on insulin biosynthesis and secretion; (5) studies on the secretion, metabolism and clinical usefulness of the proinsulin C-peptide; (6) finally, the biosynthesis of glucagon and other peptide hormones and the general significance of precursor forms.
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PMID:Biosynthesis of insulin and glucagon: a view of the current state of the art. 78 79

The epoxyeicosatrienoic acids (EETs) were discovered as products of a cyclooxygenase/lipoxygenase-independent, cytochrome P-450 catalyzed metabolism of arachidonic acid (AA) termed the "epoxygenase" pathway. The rat hypothalamus is able to synthesize EETs from exogenous AA, and 5,6-EET has been found to release the neuropeptide somatostatin (SRIF) from hypothalamic nerve terminals of the median eminence (ME). In the present study, hypothalami from male rats were examined for the presence of endogenous EETs, using chemical, chromatographic, and mass spectral analysis procedures. The samples were initially separated in a C18 Sepralyte column, fractionated on TLC plates, and purified by reverse phase HPLC. Thereafter, they were esterified (pentafluorobenzyl esters) and subjected to negative ion chemical ionization/gas chromatography (GC)/mass spectral (MS) analysis. The GC retention time and the MS fragmentation patterns revealed the presence of a mixture of 8,9-, 11,12- and 14,15-EETs; instability of 5,6-EET during the isolation protocol precluded its identification. Total hypothalamic EET concentration was estimated to be 120 ng/g wet tissue. The 8,9-regiosomer released SRIF from ME nerve terminals with an ED50 of 5 x 10(-12) M; Dopamine (DA) and the D2 receptor agonist PPHT, but not the D1 receptor agonist SKF-38393, induced SRIF release from the ME. This effect was blocked by clotrimazole and ketoconazole, two inhibitors of microsomal cytochrome P-450 function and AA epoxygenase in particular. In contrast, the inhibitors failed to affect the increase in SRIF release induced by 8,9-EET. These results indicate that: 1) in addition to cyclooxygenase and lipoxygenase products, epoxygenase metabolites of AA are endogenous compounds of the hypothalamus, and 2) EETs may mediate the increase in SRIF release from hypothalamic neurons induced by the interaction of DA with D2 receptors.
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PMID:Epoxygenase products of arachidonic acid are endogenous constituents of the hypothalamus involved in D2 receptor-mediated, dopamine-induced release of somatostatin. 196 82

In male rats exogenous growth hormone (GH) (5 mg . kg-1, twice a day for 7 days) reduced (p less than 0.05) the in vitro hepatic microsomal metabolism of ethylmorphine (EM) and hexobarbital (HB) by 59 and 33%; aniline (AN) metabolism and microsomal P-450 levels were unaltered but GH reduced (p less than 0.001) NADPH-cytochrome c reductase by 17%. GH had no effects in females. Castrated males receiving subreplacement doses of testosterone propionate (2 mg, three times weekly) were injected (280 micrograms . kg-1, three times a day for 4 days) with somatostatin (SS), an inhibitor of GH release: EM and HB metabolism was increased (p less than 0.01) 8 and 18%; AN hydroxylation and P-450 levels were unchanged; the reductase was elevated (p less than 0.01) 9%. In nonandrogenized castrates, SS effected greater changes: EM and HB metabolism was increased (p less than 0.01) 47 and 21%; AN metabolism and P-450 levels were unchanged; the reductase was increased (p less than 0.01) 27%. Conversely, SS had no effects in intact males at doses up to 1120 micrograms . kg-1, three times a day for 4 days. These data support the view that endogenous GH is a modulator of "feminized" drug metabolism in the adult male and that it is antagonized by testosterone. Attempts to inhibit drug metabolism with SS in the female were unsuccessful and may reflect the ineffectiveness of the preparations as they failed to inhibit growth in young rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of somatostatin and testosterone on the hepatic monooxygenase system in castrated male rats. 285 84

The biologically active forms of somatostatin, somatostatin-14 (SS-14) and somatostatin-28 (SS-28) arise by post-translational cleavage of prosomatostatin. Prosomatostatin in turn is derived from a larger precursor, preprosomatostatin. We have previously reported the structure of a complementary DNA molecule encoding rat preprosomatostatin. The nucleotide sequence of this cDNA indicated that SS-14 and SS-28 are located at the carboxy-terminus of a 116 amino acid precursor. At the amino-terminus of the precursor is a hydrophobic region characteristic of a leader or pre-sequence. Sequential Edman degradations of cell-free translation products synthesized in the presence of microsomal membranes indicate that preprosomatostatin is cleaved within the endoplasmic reticulum to form prosomatostatin, a precursor of 92 amino acids. To begin to elucidate the factors which regulate the expression of the rat somatostatin gene, we have determined the sequence of the gene isolated from recombinant bacteriophage libraries. The gene spans 1.2 kilobases in length and is interrupted within the coding sequence of prosomatostatin by a single intron of 630 bases. A variant of the Goldberg-Hogness promotor, TTTAAA, is located 31 bases upstream from the transcriptional start point. A repetitive sequence was identified in the 5' region of the gene within 650 bases of the promoter. The nucleotide sequence of this region reveals an alternating GT sequence 42 bases in length characteristic of DNA with Z-forming potential. Such sequences are thought to influence the expression of other eukaryotic genes.
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PMID:Biosynthesis of rat preprosomatostatin. 286 39

We have previously demonstrated the presence of specific binding sites for somatostatin on plasma membranes from pancreatic acinar cells. In the present study we attempted to characterize the fate of receptor-bound 125I-[Tyr11]somatostatin. Internalization of somatostatin was rapid (reaching a plateau at 20% of the cell-associated specific radioactivity) and temperature dependent. To follow the processing of bound somatostatin, acini were incubated with 125I-[Tyr11]somatostatin at 5 degrees C during 16 h then, after washing, incubated at 37 degrees C for 90 min in fresh medium. Surface-bound somatostatin decreased rapidly, whereas radioactivity increased in the cell interior and the incubation medium. Intracellular and membrane-bound radioactivity was mainly intact 125I-[Tyr11]somatostatin. Degradation occurred at the plasma membrane level and led to iodotyrosine production. After 15 min of incubation, 15% of the initially surface-bound 125I-[Tyr11]somatostatin was compartmentalized within the cell, mainly in the microsomal fraction. After 30 min, a significant increase in radioactivity appeared in the nuclear fraction. These results indicate that the major part of somatostatin cellular degradation takes place at the plasma membrane level. Within the cell, somatostatin is routed to the nucleus via particular fractions sedimenting with microsomal vesicles.
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PMID:Processing of receptor-bound somatostatin: internalization and degradation by pancreatic acini. 288 91

Previous studies with heterogeneous populations of pancreatic cells have provided evidence for the presence of somatostatin (SRIF) receptors in cytosol and secretion vesicles, as well as the plasma membrane. To examine the distribution of SRIF receptors between soluble and membrane fractions in a homogeneous pancreatic islet cell population, we have used the clonal RINm5F insulinoma cell line. These cells contain specific, high affinity binding sites for [125I-Try11]SRIF on the cell surface, and occupancy of these sites by SRIF and SRIF analogs correlates with inhibition of insulin secretion. Stable, steady state binding was achieved using both intact cells and membranes by performing binding incubations with [25I-Tyr11]SRIF at 22 C. Half-maximal inhibition of [125I-Tyr11]SRIF binding occurred with 0.21 +/- 0.11 nM SRIF in membranes and 0.35 +/- 0.30 nM SRIF in cells. In contrast, the binding of [125I-Tyr11]SRIF to cytosolic macromolecules was not reduced by concentrations of SRIF as high as 100 nM, demonstrating that this binding was of much lower affinity. RINm5F membranes were further purified using a Percoll gradient to prepare a microsomal fraction, which was enriched in adenylate cyclase activity, and a secretory granule fraction, which was enriched in insulin. [125I-Tyr11]SRIF binding to the microsomal fraction (3.8 +/- 0.3 fmol/mg) was 3 times higher than to secretion granules (1.2 +/- 0.2 fmol/mg). Thus, high affinity SRIF binding sites were most abundant in microsomal membranes and were low or undetectable in secretory granules and cytosol. To determine whether translocation of SRIF receptors to the plasma membrane accompanied insulin secretion, we examined the effects of various insulin secretagogues on [125I-Tyr11]SRIF binding to intact cells. Leucine (20 mM), glyceraldehyde (15 mM), forskolin (1 microM), and glucagon (1 microM) stimulated insulin release 1.5- to 4.0-fold in different experiments. However, these secretagogues did not increase [125I-Tyr11]SRIF binding. In summary, our results indicate that high affinity SRIF receptors in RINm5F cells are located primarily on the plasma membrane and that the concentration of SRIF receptors at the cell surface is independent of the secretory activity of the cells.
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PMID:Distribution of somatostatin receptors in RINm5F insulinoma cells. 289 29

Evidence is presented for a precursor to somatostatin that is 10-12 times larger than the authentic secreted hormone. mRNA from angler fish (Lophius americanus) islets of Langerhans was translated in the wheat germ cell-free system and the products were identified by immunoprecipitation with specific antibodies to somatostatin followed by sodium dodecyl sulfate gel electrophoresis. One 18,000-dalton polypeptide was specifically immunoprecipitable. Competition experiments showed that authentic somatostatin competed with the 18,000-dalton molecule for antibody binding. When dog pancreas microsomal membranes were present during translation, an additional polypeptide of 16,000 daltons was also immunoprecipitable. Comparison of their tryptic peptides demonstrated that the 16,000-dalton polypeptide was derived from the 18,000-dalton one. Tryptic peptide analysis of somatostatin and the 18,000-dalton precursor demonstrated that the 18,000-dalton polypeptide contains the authentic somatostatin amino acid sequence and suggests that it is located at the carboxyl terminus of the precursor molecule and is preceded by a basic amino acid.
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PMID:In vitro biosynthesis of fish islet preprosomatostatin: evidence of processing and segregation of a high molecular weight precursor. 610 4

mRNA isolated from bovine hypothalami was used to direct the in vitro synthesis of a precursor to the tetradecapeptide somatostatin. When a rabbit reticulocyte lysate translation system supplemented with [35S]cysteine was used, a protein of apparent molecular weight 15 500 was identified as preprosomatostatin by reaction with specific rabbit antibodies. Cotranslational addition of dog pancreas microsomal membranes yielded an unglycosylated pro form of 14 500 daltons, implying the removal of a short signal sequence.
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PMID:In vitro messenger ribonucleic acid directed synthesis and processing of an immunologically identified precursor to tetradecapeptide somatostatin from bovine hypothalamus. 612 66

The tetradecapeptide hormone somatostatin arises from proteolytic processing of a large precursor, pre-prosomatostatin. Studies of other hormone precursors predict that the NH2 terminus of pre-prosomatostatin comprises a leader, or signal, region which is cleaved during its translation. Such co-translational cleavage would generate prosomatostatin. In these studies, we present the complete sequence of rat pre-prosomatostatin, deduced from the nucleotide sequence of cDNAs derived from a somatostatin-rich medullary thyroid carcinoma. These findings indicate that rat pre-prosomatostatin contains 116 amino acids (12,737 daltons). Cell-free translations of medullary thyroid carcinoma mRNA with dog pancreas microsomal membranes were performed to identify the cleavage point of the leader region from prosomatostatin. Partial microsequencing data indicates that the cleavage occurs between the glycine and alanine at positions 24 and 25 of pre-prosomatostatin. Thus, rat prosomatostatin contains 92 amino acids (10,388 daltons). Comparison of the amino acid sequences of the rat and human pre-prosomatostatins reveals only four amino acid substitutions. In view of the high degree of homology between rat and human pre-prosomatostatin, we expect a similar cleavage site and NH2-terminal structure for human prosomatostatin. The high level of conservation between rodents and humans of the entire pre-prosomatostatin molecule further suggests the possibility of biologic functions of the NH2-terminal portions of prosomatostatin.
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PMID:Rat pre-prosomatostatin. Structure and processing by microsomal membranes. 613 71


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