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 neurotransmitter of the non-adrenergic non-cholinergic inhibitory innervation of the stomach is still unknown. We studied the effect of a series of neurotransmitter candidates, ATP, [Leu]enkephalin and [Met]enkephalin, somatostatin, neurotensin and VIP, in the rat gastric fundus and compared these effects with the response to electrical stimulation of the non-adrenergic non-cholinergic inhibitory neurons. Rats of both sexes were treated with reserpine (5 mg . kg-1 intraperitoneally) 24 h before killing. Longitudinal muscle strips of the gastric fundus were prepared and mounted between parallel platinum electrodes in Krebs solution containing atropine 10(-6) M and serotonin 3.10(-6) M. A maximal relaxatory response was obtained on transmural stimulation of the strips at supramaximal voltage, 1 msec and 5 Hz. ATP (10(-6)-10(-3) M) elicited a biphasic response, a small relaxation followed by a contraction. The maximal relaxatory response induced by ATP was much lower than that induced by transmural stimulation during 45 sec (37.3% versus 166.2%, where 100% is the maximal contractile response to ATP, n = 17). Desensitization to ATP did not influence the relaxation induced by transmural stimulation. [Met]enkephalin, [Leu]enkephalin and naloxone did not change the tone of the strips or the amplitude of the electrically induced relaxation. Somatostatin had no influence while neurotensin induced a concentration-dependent contraction from 10(-9) M or 10(-8) M on. VIP (10(-10)-3.10(-8) M) induced a concentration-dependent relaxation. The maximal relaxation induced by VIP was 120.8% of that induced by transmural stimulation (n = 16). The relaxation induced by VIP 10(-8) M, left in contact with the tissue for 10 min, was comparable to that induced by transmural stimulation during 10 min, except for a lag time of more than 10 sec after the addition of VIP. The relaxation induced by VIP was not influenced by tetrodotoxin, phentolamine or propranolol. The peptidase trypsin (10(-6) M) antagonized the relaxation by exogenously added VIP but did not influence the electrically induced relaxation. The results obtained in this study show that, of the substances tested, only VIP mimics the relaxation induced by stimulation of the inhibitory non-adrenergic non-cholinergic neurons in the rat gastric fundus; VIP therefore seems a reasonable candidate as neurotransmitter of these neurons.
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PMID:Study on the possible neurotransmitter of the non-adrenergic non-cholinergic innervation of the rat gastric fundus. 287

Calcium-dependent, tetrodotoxin (1 microM)-sensitive release of somatostatin-like immunoreactivity (SRIF-LI) could be evoked by electrical field stimulation of vibratome-cut cerebral cortical slices superfused in vitro. The release of SRIF-LI from cortical slices was frequency-dependent, and showed facilitation between 5 and 25 Hz. Release was also current-dependent and above a threshold of 10 mA increased to plateau at 80 mA. Addition of peptidase inhibitors did not improve the recovery of SRIF-LI, and HPLC analysis of the released material showed that over 95% of SRIF-LI released corresponded to SRIF-14 (SRIF-28).
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PMID:In vitro release of somatostatin from cerebral cortical slices: characterization of electrically evoked release. 289 75

Degradation of LHRH and [D-Ser(tBu)6,des-Gly-NH10(2)]LHRH ethylamide (LHRH-A), during incubation with high-speed supernatants of rat testes, as assessed by reversed-phase (RP)-HPLC fractionation of the iodinated peptides and by radioimmunoassays for LHRH or LHRH-A, was principally due to a neutral 43 000 Da peptidase with apparent Km values at 25 degrees C of 0.15 microM for LHRH and 1.19 microM for LHRH-A. The peptidase was inhibited by sulphydryl reagents, TLCK, 1,10-phenanthroline, EDTA, bacitracin, other LHRH analogues, oxytocin, [Lys8]vasopressin and somatostatin. It was predomantly located in seminiferous tubule supernatants (98% of recovered activity), with much lower levels in interstitial fluid (2%), interstitial tissue or testicular particulate fractions (less than 0.8%). Extracts of cultured immature Sertoli cells produced LHRH- and LHRH-A-degradation profiles, as assessed by RP-HPLC, that were identical to those produced by testicular supernatants. Similar levels of peptidase activity/mg protein were observed in immature and adult rat testes. These studies indicate that the principal LHRH-peptidase in the rat testis is produced by cells of the seminiferous epithelium, chiefly the Sertoli cell, and may play an important role in regulating the activity of LHRH and other peptide hormones in the testis.
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PMID:Degradation of luteinizing hormone-releasing hormone (LHRH) and an LHRH agonist by the rat testis. 351 17

The cytosol fraction of rat pancrease can bind [3H] estradiol specifically and extensively. In contrast to the rat uterus, the binding protein in pancreas requires an accessory factor as a coligand in the steroid-binding reaction. Removal of this accessory factor by passage of the cytosol through CM Affi-Gel blue columns renders eluate fractions virtually incompetent with respect to binding of [3H]estradiol (10 nM). Certain synthetic oligopeptides such as N-benzoyl-L-argininyl-p-nitroanilide, as well as an endogenous accessory factor, can reactivate binding of [3H]estradiol. Thus, localization of the protein that binds [3H]estradiol following chromatography with CM Affi-Gel blue columns can be determined readily by assaying eluate fractions in the absence and presence of either accessory factor or N-benzoyl-L-argininyl-p-nitroanilide. Addition of somatostatin (tetradecapeptide referred to as SRIF14; somatotropin release inhibiting factor) to the activatable, but incompetent, eluate fractions, also enhanced binding of [3H]estradiol. The effect of SRIF14 was biphasic. The threshold concentration required for activation of [3H]estradiol binding was about 1 microM, and maximal stimulation occurred at 25 microM. At higher concentrations of SRIF14, binding declined and reached basal levels at about 75 microM. The concentrations of somatostatin required for activation of binding of [3H]estradiol in vivo may be lower than those indicated above since 1) preparations containing [3H]estradiol-binding protein also contained an SRIF14 peptidase. Following incubation of [125I-Tyr1]SRIF14 with these preparations there was loss of binding of radiolabeled peptide with SRIF14 antiserum. 2) The biphasic nature of SRIF14 activation may reflect feedback inhibition of [3H]estradiol binding by a degradation product of SRIF14. Since SRIF14 has been identified in the delta- (or D-) islet cells of the pancreas, and in concentrations that may be in the microM range, the possibility is raised that these cells serve a paracrine function with respect to acinar cell secretion.
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PMID:Somatostatin enhances binding of [3H]estradiol to a cytosolic protein in rat pancreas. Possible role of oligopeptide coligands in secretion. 613 21

Frozen sections 10 microns thick were cut from the retina of chicks which had been kept either in total darkness or in a well lit room. The sections were incubated with acetylcholinesterase before antibodies to [Leu] enkephalin, substance P or somatostatin were applied. Sections of bovine adrenals were treated similarly but they were developed only with antibodies to [Leu]enkephalin. There were low numbers of immunoreactive amacrine cells and processes when any of the three antibodies were used on sections of dark-adapted retinae. When the sections were treated with acetylcholinesterase, however, the enkephalin-like and substance P-like immunoreactivity was enhanced while there was no effect on somatostatin. Counts of immunofluorescent cells indicated that the numbers had increased to levels like those found in light-adapted retinae. The adrenal also showed an enhanced enkephalin-like immunoreaction after treatment with the enzyme. Incubation with buffer alone or with enzyme together with 10 mM acetylcholine abolished the reaction. Acetylcholinesterase treatment of sections from light-adapted retinae had no discernible effect on the already high immunoreaction found using any of the three antisera. It is concluded that the peptidase activity of acetylcholinesterase has the capacity to hydrolyze proteins of which some may be the precursor molecules for the enkephalins and substance P. Since the amacrine cells that contain the enkephalin-like and the substance P-like immunoreactivity were found to contain acetylcholinesterase, it is possible that the action found here in vitro represents a physiological function of the enzyme. The immunoreactivity on which there was no effect, somatostatin, does not co-exist with acetylcholinesterase. A second conclusion that may be drawn from these data is that the dark-adapted retinae lose immunoreactive peptide because of the rate of processing; the results suggest that there is adequate precursor molecule available to maintain "control" levels.
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PMID:Treatment of sections of chick retina with acetylcholinesterase increases the enkephalin and substance P immunoreactivity. 620 21

Growth hormone (GH)-releasing activity has been detected in extracts of carcinoid and pancreatic islet tumors from three patients with GH-secreting pituitary tumors and acromegaly. Bioactivity was demonstrated in 2 N acetic acid extracts of the tumors using dispersed rat adenohypophyseal cells in primary monolayer culture and a rat anterior pituitary perifusion system. The GH-releasing effect was dose responsive and the greatest activity was present in the pancreatic islet tumor. Small amounts of activity were also found in two other tumors (carcinoid and small cell carcinoma of lung) unassociated with GH hypersecretion. Each of the tumors contained somatostatin-like immunoreactivity but the levels did not correlate with the net biologic expression of the tumor. Sephadex G-75 gel filtration indicated the GH-releasing activity to have an apparent molecular size of slightly greater than 6,000 daltons. The GH-releasing activity was adsorbed onto DEAE-cellulose at neutral pH and low ionic strength, from which it could be eluted by increasing ionic strength. The GH-releasing activity was further purified by high pressure liquid chromatography using an acetonitrile gradient on a cyanopropyl column to yield a preparation that was active at 40 ng protein/ml. Partially purified GH-releasing activity, from which most of the bioactive somatostatin had been removed, increased GH release by pituitary monolayer cultures to five times base line. Enzymatic hydrolysis studies revealed that the GH-releasing activity was resistant to carboxypeptidase, leucine-aminopeptidase, and pyroglutamate-amino-peptidase but was destroyed by trypsin and chymotrypsin, indicating that internal lysine and/or arginine and aromatic amino acid residues are required for biologic activity and that the NH2-terminus and CO9H-terminus are either blocked or not essential. The results provide an explanation for the presence of GH-secreting tumors in some patients with the multiple endocrine neoplasia syndrome, type I, and warrant the addition of GH-releasing activity to the growing list of hormones secreted by tumors of amine precursor uptake and decarboxylation cell types.
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PMID:Partial purification and characterization of a peptide with growth hormone-releasing activity from extrapituitary tumors in patients with acromegaly. 624 40

The considerable expansion in studies on the enzymic inactivation of thyrotrophin-releasing hormone, luteinizing hormone-releasing hormone and somatostatin (growth hormone release-inhibiting hormone) has necessitated a re-evaluation of the peptidase enzymes responsible. Through the use of new methods such as high-performance liquid chromatography and the development of artificial enzyme substrates, it has been possible to clarify the mechanisms of enzyme cleavage of these hypothalamic regulatory hormones and to attempt purification of the peptidases. This has brought about a renewed interest in the physiological significance of the enzymes, as well as their role in biotransformation of the hypothalamic hormones. From such studies, the information gained may be used in the design of agonist and antagonist analogues, as well as providing details of the mechanisms of action of such analogues through their increased stability to enzymic degradation. The characterization of corticotrophin-releasing factor and growth hormone-releasing factor will provide a new field for the application of peptidase inactivation to analogue design. Similarly, future examination of the peptidases inactivating the hypothalamic hormones in certain clinical conditions may give new insight into the significance of the enzymes in pathological conditions. Identification of these enzymes, investigation of their localization, properties and functions and assessment of their contribution to the control of hormone action may yield valuable insight into the physiology and pathology of the hypothalamic regulatory hormones.
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PMID:Enzymic inactivation of hypothalamic regulatory hormones. 641 8

Previous functional studies show that somatostatin (SS) interacts with specific receptors to inhibit relaxation in gastric smooth muscle cells. There are no ligand binding studies, and it is unknown which of the five subtypes of SS receptors mediates the action. Dispersed gastric smooth muscle cells from guinea pig bound both 125I-labeled SS-14 and 125I-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2 (where Nal indicates N-naphthylalanine) (cyclo-SS-8), a synthetic peptidase-resistant octapeptide SS analogue. SS-28 and SS-14, cyclo-SS-8, and SS analogue D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol [SMS-(201-995) (octreotide)] inhibited 125I-cyclo-SS-8 binding with relative potencies of SS-28 = cyclo-SS-8 = SMS-(201-995) (octreotide), and the binding was not affected by the addition of protease inhibitors. SS-14 caused inhibition only in the presence of protease inhibitors. Ligand analysis demonstrated a two-binding-site model. Analysis of the relationship between biological function and binding suggested the high-affinity sites mediated the relaxant action of SS. 5'-Guanylylimidodiphosphate [Gpp-(NH)p] inhibited binding by reducing the affinity of the high-affinity site. Six SS-8 analogues that distinguish SS subtypes showed that 125I-SS-14 bound to somatostatin receptor subtype 3 (SSTR3). The results demonstrated that gastric smooth muscle cells possess distinct receptors for SS of the SSTR3 subtype. Occupation of these sites inhibits relaxation in gastric smooth muscle cells. Modulation between the high- and low- affinity binding states of SSTR3 is at least partially mediated by activation of guanine nucleotide regulatory proteins.
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PMID:Somatostatin receptor subtype 3 mediates the inhibitory action of somatostatin on gastric smooth muscle cells. 776 57

Sixty-four kinds of cell lines were examined as to their ability to degrade glucagon using conditioned-media obtained from their protein-free cultures. Two human tumor cell lines were shown to produce this activity, and the cell line, HPC-YO, established from a human pancreatic carcinoma was shown to produce the highest level of activity. The glucagon-degrading enzyme (GDE) was purified from HPC-YO conditioned-medium by a combination of ion-exchange, gel filtration, and hydroxylapatite column chromatographies. The purified GDE also degraded vasoactive intestinal polypeptide (VIP) and secretin, however, it did not cleave EGF, gastrin, insulin, somatostatin, substance P, neurotensin, or growth hormone. The molecular weight of GDE is 83,000, as determined on SDS-polyacrylamide gel electrophoresis. The N-terminal amino acid sequence of GDE was blocked, and the five partial amino acid sequences obtained on lysyl-endopeptidase digestion were determined to be N-L-T-E-E-Y-D-V-S-D-G-E-I-E-L-L-Y-E-K, V-E-T-Y-Y-D-L-L-F-E-K, L-Y-W-F-L-D-E-A-K, S-N-S-T-S-Y-V-K, and Y-Y-A-S-T-S-Y-D-D-T-Y-K. The same or homologous amino acid sequences have not been found in known proteins, demonstrating that GDE is a novel peptidase that degrades the secretin family: glucagon, VIP, and secretin.
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PMID:A novel proteinase, glucagon-degrading enzyme, secreted by a human pancreatic cancer cell line, HPC-YO. 777 1

The principles involved in the fabrication and use in vivo of antibody microprobes are described. These devices have shown that immunoreactive (ir)-substance P and ir-neurokinin A are released in the region of the substantia gelatinosa of the spinal cord when impulses arrive in nociceptors. Particularly with ir-neurokinin A, rapid inactivation does not appear to occur, resulting in the released neuropeptides accessing sites relatively remote from sites of release. Microprobes have also provided evidence that the sites accessed by ir-substance P are controlled by spinal cord peptidases and that peptidase inhibition by the endogenous neuropeptide calcitonin gene-related peptide expands the distribution of sites reached. Inflammatory joint disease results in a relatively massive central release of ir-substance P when the damaged joints are flexed or compressed. Antibody microprobe studies of the spinal release of ir-galanin have favored release from intrinsic spinal neurons rather than from primary afferent terminals following peripheral noxious stimuli. Immunoreactive-somatostatin was found to be released following noxious thermal but not noxious mechanical peripheral stimuli but it is uncertain whether this results from release predominantly from primary afferents or intrinsic spinal neurons. Studies using antibody microprobes inserted into the brain have detected the release of ir-substance P in the ventral region of the striatum following administration of amphetamine. Microprobes have also followed peptide release from striatal terminals in substantia nigra and have provided evidence of a basal presence of ir-neurokinin A but not of substance P. Depletion of the dopamine input to the striatum, or blockade of dopamine receptors, caused considerable reduction of ir-neurokinin A released within the substantia nigra.
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PMID:Probing the brain and spinal cord with neuropeptides in pathways related to pain and other functions. 785 15


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