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)

Rolipram (4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone) represents a new class of specific low Km cAMP phosphodiesterase (PDE) inhibitors. This compound enhances basal, hormone- and forskolin-elicited cAMP accumulation in prolactin (PRL) producing rat pituitary adenoma (GH4C1) cells in culture (ED50 = 5.10(-8) M). This effect is due to a selective inhibition of the low Km cAMP PDE (type III), since neither basal nor hormone-stimulated adenylate cyclase (AC) nor the Ca2+/calmodulin-dependent PDE were affected by rolipram. The drug enhanced vasoactive intestinal polypeptide (VIP)-stimulated PRL-secretion, while thyroliberin (TRH)- and 12-0-tetradecanoyl phorbol-13-acetate (TPA)-elicited PRL egress were slightly reduced indicating a cAMP-mediated reduction of protein kinase C (PK-C) mediated PRL release. Interestingly, inhibition of PRL secretion by somatostatin (SRIH) was completely suppressed suggesting cAMP-mediated inactivation of some GTP-binding protein(s) of the alpha i family (G alpha i2 or Gk). Rolipram did not affect phosphoinositide metabolism (i.e. IP3 accumulation), neither acutely nor after long term administration. Rolipram, like the cAMP PDE inhibitor Ro 20-1724, did not influence AC and PDE I, but dose-dependently inhibited PDE III activity. Long term incubation of GH4C1 cells with rolipram in the presence of noradrenaline (NA) exerted a marginal decrease of beta-receptor number, AC activation and cAMP accumulation, while Ro 20-1724 brought about a marked down-regulation and desensitization of the AC complex. In summary, rolipram selectively interacts with PDE III in rat pituitary adenoma cells in culture and does not result in beta-adrenoceptor AC downregulation. These features are not shared by the other drugs tested.
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PMID:The pharmacodynamic action of the cyclic AMP phosphodiesterase inhibitor rolipram on prolactin producing rat pituitary adenoma (GH4C1) cells. 217 76

Endocrine tumors of the gastroenteropancreatic (GEP) axis elaborate excessive amounts of peptides that are potent intestinal secretagogues. The actions of these peptides on intestinal transport of water and electrolytes lead to the accumulation of fluid in the intestinal lumen and diarrhea. One of the most clinically relevant secretagogues is vasoactive intestinal polypeptide (VIP). Other relevant secretagogues elaborated from tumors are serotonin, prostaglandins, and kinins. Sandostatin (octreotide, Sandoz, Basle, Switzerland), a long-acting octapeptide analog of somatostatin, inhibits experimentally induced intestinal secretion and has been used successfully to treat patients with secretory diarrhea refractory to other pharmacotherapy. The effective dose is in the range of 50 to 200 micrograms, given subcutaneously two or three times daily. The mechanism for the inhibitory effect on secretion is not clearly understood but it appears to involve inhibition of the adenylate cyclase-cyclic adenosine monophosphate system as well as interference with calcium as an intercellular mediator of enterocyte secretion. A particularly interesting use of this drug has been to treat the watery diarrhea seen in patients with acquired immunodeficiency syndrome. It is also effective in other types of secretory diarrhea not associated with endocrine tumors. These include diabetic diarrhea, idiopathic secretory diarrhea of infancy, and high output ileostomy diarrhea.
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PMID:Treatment of endocrine and nonendocrine secretory diarrheal states with Sandostatin. 220 86

Mechanisms regulating peptidergic, noradrenergic and cholinergic development were compared in dissociated cell cultures of neonatal rat sympathetic ganglia. The majority of cultured neurons contained at least two neurotransmitters and many neurons contained three or more. These studies were undertaken to determine whether co-existing transmitters were co-ordinately regulated by the environment. Co-culture of sympathetic neurons with ganglion non-neuronal cells increased substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity. Conversely, elimination of non-neuronal cells virtually abolished neuronal expression of substance P and choline acetyltransferase and increased somatostatin and tyrosine hydroxylase. Consequently, under these conditions, somatostatin and tyrosine hydroxylase were similarly regulated, whereas substance P was associated with choline acetyltransferase. By contrast, stimulation of adenylate cyclase or treatment with membrane-permeable adenosine 3',5'-phosphate analogs increased tyrosine hydroxylase and decreased choline acetyltransferase, but had no effect on substance P or somatostatin levels. Moreover, potassium- or veratridine-induced membrane depolarization increased tyrosine hydroxylase but decreased substance P, somatostatin and norepinephrine levels. However, inhibition of neurotransmitter release with magnesium or calcium-free medium prevented the decrease in norepinephrine levels but not the decrease in substance P and somatostatin. Consequently, the effects of membrane depolarization on peptide levels cannot be ascribed to release and subsequent depletion of substance P and somatostatin and must result from decreased net synthesis (synthesis minus catabolism) of the transmitters. Nerve growth-factor treatment also differentially regulated transmitter metabolism; nerve growth factor increased protein-specific activities of tyrosine hydroxylase and choline acetyltransferase but did not increase the protein-specific content of substance P and somatostatin. Quantitative transmitter expression was also influenced by neuron density; increasing density elevated substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity per neuron. Finally, culture of sympathetic neurons in a defined (serum-free) medium also altered some but not all traits, decreasing substance P, somatostatin and choline acetyltransferase without any change in tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons. 241 73

Corticotropin (ACTH)-releasing factor, vasoactive intestinal peptide, and catecholamines--hormones that stimulate ACTH secretion and cAMP generation--increased cytosolic calcium in AtT-20 cells. The increase in intracellular calcium is presumably a consequence of the stimulated cAMP synthesis, since forskolin, an activator of the catalytic unit of adenylate cyclase, and the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cAMP) also increased the cytosolic levels of this ion. Pretreatment with somatostatin, a neuropeptide that inhibits stimulation of the adenylate cyclase system and the secretion of ACTH blocked the increase of cytosolic calcium. The effect of 8Br-cAMP, which bypasses the cyclase, was not inhibited by somatostatin pretreatment. The source of the increased calcium appears to be mainly extracellular. This is indicated by the inability of the secretagogues to increase cytosolic calcium in a medium deprived of this ion or in the presence of blockers of voltage-gated calcium channels. The involvement of calcium channels in the calcium rise evoked by the secretagogues was supported by experiments using the whole-cell patch-clamp technique. In these experiments 8Br-cAMP increased voltage-dependent calcium currents. These results suggest the following chain of events in the receptor-mediated elevation of cytosolic calcium and the concomitant release of ACTH from AtT-20 cells: hormone-receptor binding----cAMP synthesis----protein kinase activation----calcium channel activation----increase in cytosolic calcium----many steps----ACTH release. Phorbol myristate acetate, a compound which does not stimulate cAMP generation but enhances the release of ACTH in AtT-20 cells, decreased the cytosolic calcium level.
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PMID:Hormone secretagogues increase cytosolic calcium by increasing cAMP in corticotropin-secreting cells. 241 78

Somatostatin and carbachol receptors are believed to be negatively coupled to adenylate cyclase in AtT-20 mouse pituitary tumor cells by an inhibitory guanine nucleotide-binding regulatory subunit. Activation of these receptors causes inhibition of cyclic AMP synthesis and adrenocorticotropin (ACTH) secretion stimulated by a variety of hormones. Secretion in response to several pharmacological agents, which do not increase AtT-20 cyclic AMP levels, is also antagonized by both somatostatin and carbachol. Inasmuch as ACTH secretion in response to all stimulants is dependent on extracellular calcium, the possibility that somatostatin and carbachol block calcium entry was investigated by observing the effects of these agents on the activity of the calcium channel activator, BAY-K-8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4- (2-trifluoromethylphenyl)-pyridine-5-carboxy-late] in AtT-20 cells. In first characterizing the effect of BAY-K-8644, it was noted that the channel agonist at 10(-10) to 10(-6) M itself rapidly increased basal ACTH secretion; higher concentrations (10(-4) M) reduced basal, (-)-isoproterenol, phorbol ester, 8-Br-cAMP and K+-stimulated secretion. BAY-K-8644 did not alter basal formation of cyclic AMP. The secretory response to BAY-K-8644 was dependent on extracellular calcium, and was inhibited by the calcium channel antagonist, nifedepine. When coapplied with (-)-isoproterenol, phorbol ester and 8-Br-cAMP, at a concentration which optimally stimulated ACTH secretion, BAY-K-8644 had an additive effect; the secretory responses to K+ (50 mM) or the calcium ionophore, A-23187, on the other hand, were potentiated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of adrenocorticotropin secretion from AtT-20 cells by the calcium channel activator, BAY-K-8644, and its inhibition by somatostatin and carbachol. 241 8

A 40-yr-old man who had acromegaly and hyperthyroidism due to a GH/TSH-secreting pituitary adenoma is described. Serum free T4 was 2.8 ng/dl, free T3 was 1.1 ng/dl, and TSH was 1.2-1.5 microU/ml; the latter was measured in an immunoradiometric assay with a sensitivity of 0.07 microU/ml. Serum TSH was immunologically identical to standard TSH and did not decrease during a T3 suppression test. Serum free alpha-subunit and the molar alpha-subunit to TSH ratio were high (6.1 ng/ml and 31.2, respectively). TRH administration induced significant increases in both GH (+129%) and alpha-subunit (+156%) levels. Conversely, dopamine infusion resulted in a decrease in serum GH (-66%) and alpha-subunit (-43%) levels, and subsequent administration of the dopamine antagonist sulpiride induced significant increases in both GH and alpha-subunit (+393% and +106%, respectively). Similarly, somatostatin infusion inhibited GH (-43%) and alpha-subunit (-61%) secretion. Serum TSH levels were not affected by TRH, dopamine, or somatostatin. The biological to immunological activity ratio of serum TSH purified by immunoaffinity chromatography and measured in an adenylate cyclase assay was significantly increased compared to that in serum from hypothyroid or euthyroid subjects [biological to immunological activity ratio, 6.9 +/- 0.2 (+/- SD) vs. 4.4 +/- 1.1; P less than 0.001]. In gel chromatography, the apparent mol wt of the patient's TSH was smaller than that of the controls. After adenomectomy, all of the altered parameters of pituitary function became normal. Double gold particle immunostaining of the adenomatous tissue showed that all of the cells contained secretory granules positive for GH and alpha-subunit, while very few cells were positive for TSH beta as well as GH and alpha-subunit. These data indicate that in this patient serum TSH had an apparent mol wt smaller than that of normal TSH and an increased biological activity which, along with the autonomous TSH secretion, account for hyperthyroidism in the presence of low normal TSH levels; alpha-subunit originated from the same adenomatous cells that secreted GH but not TSH, thus explaining the in vivo observation that alpha-subunit responses to several agents were dissociated from TSH responses and parallel to GH responses; and TSH and GH were colocalized in a minority of the neoplastic cells.
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PMID:Endocrine, biochemical, and morphological studies of a pituitary adenoma secreting growth hormone, thyrotropin (TSH), and alpha-subunit: evidence for secretion of TSH with increased bioactivity. 241 56

The mechanisms by which somatostatin (SRIF) inhibits CRF-induced ACTH secretion from AtT20 cells were characterized by comparing the effects of SRIF on cAMP production, adenylate cyclase activity, and activation of cAMP-dependent protein kinase isoenzymes with its effects on ACTH release. In isolated membranes, CRF (100 nM) stimulated adenylate cyclase activity 4- to 5-fold. SRIF inhibited CRF-stimulated adenylate cyclase in a concentration-dependent manner. However, maximal inhibition was 50%. SRIF did not inhibit basal adenylate cyclase or forskolin-stimulated cyclase in the absence of guanine nucleotides and had only small effects on forskolin-stimulated cyclase when assayed in the presence of guanine nucleotides. CRF (100 nM) induced small rises (2-fold) in intracellular cAMP levels which produced maximal ACTH release. SRIF inhibited basal and CRF-stimulated ACTH release in a concentration-dependent manner, and there was a good correlation between inhibition of ACTH release and inhibition of the activation of cAMP-dependent protein kinases in these cells. Thus, the effect of SRIF on CRF-induced ACTH release appeared to result from its effect on inhibition of adenylate cyclase. In the presence of 3-methylisobutylxanthine (MIX), CRF increased cAMP levels 20-fold and activated a greater proportion of cAMP-dependent protein kinase, but did not stimulate ACTH release more than CRF alone. Under these conditions, SRIF (100 nM) inhibited cAMP accumulation by 90%. ACTH release was also inhibited, but higher concentrations of SRIF were required to block ACTH release compared to cells incubated in the absence of MIX. Sufficient cAMP levels were achieved so that activation of cAMP-dependent protein kinases was only partially blocked. There was still sufficient cAMP to activate cAMP-dependent protein kinase to an extent equal to that seen with CRF without MIX. Similar effects of SRIF on cAMP accumulation and protein kinase activation were seen when cells were stimulated with forskolin. Our results demonstrate that SRIF inhibits ACTH release from AtT20 cells by inhibiting hormone-sensitive adenylate cyclase and thereby prevents the activation of cAMP-dependent protein kinases. However, under conditions where cAMP-dependent protein kinases are still sufficiently active to induce ACTH secretion, high concentrations of SRIF can inhibit ACTH release by a mechanism independent of cAMP-dependent protein kinase.
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PMID:Somatostatin inhibits corticotropin-releasing factor-stimulated adrenocorticotropin release, adenylate cyclase, and activation of adenosine 3',5'-monophosphate-dependent protein kinase isoenzymes in AtT20 cells. 242 87

Somatostatin reduces voltage-dependent Ca2+ current (ICa) and intracellular free Ca2+ concentration in the AtT-20/D16-16 pituitary cell line. We tested whether guanine nucleotide-binding proteins (G or N proteins) are involved in the signal transduction mechanism between the somatostatin receptor and voltage-dependent Ca2+ channels. Treatment of the cells with pertussis toxin, which selectively ADP ribosylates the GTP binding proteins Gi and Go and suppresses the ability of Gi to couple inhibitory receptors to adenylate cyclase, abolished the action of somatostatin on both ICa and intracellular free Ca2+. Intracellular application of the nonhydrolyzable guanine nucleotide analog guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), which irreversibly activates G proteins, changed the somatostatin effect on ICa from a reversible to an irreversible inhibition. Intracellular GTP[gamma S] alone caused a very slowly developing inhibition of ICa. When ICa was inhibited by GTP[gamma S] (alone or with somatostatin), it failed to respond to subsequent applications of somatostatin. The effect of GTP[gamma S] on the inhibition of ICa by somatostatin was not altered by the intracellular application of cAMP and 3-isobutyl-1-methylxanthine. The results suggest that a GTP-binding protein is directly involved in the cAMP-independent receptor-mediated inhibition of voltage-dependent Ca2+ channels.
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PMID:A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line. 243 11

A method is described for the isolation and short-term culture of canine antral gastrin (G) cells. Tissue was dispersed by enzymes and G cells enriched by elutriation and cultured for 40 h. These cultures contained 12% G cells and less than 2% somatostatin- or serotonin-containing cells. Bombesin (0.001-100 pM) potently stimulated gastrin release from cell cultures in a linear fashion over 2 h. The bombesin-specific monoclonal antibody 2A11 dose-dependently blocked bombesin stimulation. Somatostatin (0.001-1,000 nM) inhibited bombesin-stimulated gastrin release. Antibody to somatostatin (Mab S8) prevented the inhibition by exogenous somatostatin but did not alter bombesin-stimulated or basal gastrin release. The substance P (SP) analogue spantide (1 nM-1 microM) did not inhibit bombesin-stimulated gastrin release. Postreceptor activation of adenylate cyclase by forskolin and of protein kinase C by the phorbol ester, beta-TPA, caused gastrin release. The calcium ionophore A23187 also released gastrin in a dose-dependent fashion. This methodology allows enrichment and short-term culture of antral G cells; these cells have stimulatory bombesin and inhibitory somatostatin receptors, suggesting that these peptides have a direct action on antral G cells. Furthermore, G cells are activated by cAMP and calcium/phosphatidylinositol-dependent mechanisms.
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PMID:Bombesin stimulation of gastrin release from canine gastrin cells in primary culture. 243 71

Interleukin 2 (IL-2) stimulated the differentiation of human peripheral blood leukocytes into lymphokine-activated killer cells, as well as DNA synthesis of human T lymphocytes. Both effects of IL-2 could be inhibited by prostaglandin E2, a potent stimulator of adenylate cyclase; however, the inhibitory effect of prostaglandin E2 could be overcome by increased concentrations of IL-2. The opposite effects of IL-2 and prostaglandin E2 were paralleled by their respective abilities to inhibit and stimulate cAMP production in intact cells. Other agents, which inhibit adenylate cyclase directly (somatostatin, beta-endorphin, UK 14.3041) or indirectly by activation of protein kinase C (phenylephrine), could stimulate both differentiation and proliferation. None of these agents alone or in combination were as effective as maximal concentrations of IL-2. However, all agents potentiated differentiation and proliferation induced by submaximal and maximal concentrations of IL-2. Additionally, combinations of agents which stimulated protein kinase C with those that inhibited adenylate cyclase were additive in the potentiation of IL-2-induced differentiation. Neither inhibition nor potentiation of IL-2-induced lymphokine-activated killer cell differentiation was accompanied by changes in Tac expression or gamma-interferon production. The data indicate that the stimulation of lymphokine-activated killer cell differentiation and lymphocyte proliferation in human cells share a common initial biochemical signal. Although the inhibition of adenylate cyclase is not sufficient to maximally stimulate either process and cannot bypass the requirement for IL-2, modulation of this enzyme complex, positively or negatively, can regulate the ultimate physiologic response to IL-2.
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PMID:Potentiation of lymphokine-activated killer cell differentiation and lymphocyte proliferation by stimulation of protein kinase C or inhibition of adenylate cyclase. 244 68


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