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)

GH secretion has been thought traditionally to be regulated by the two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin (SRIF). Recent evidence has suggested that other factors may be involved. These factors include the natural ligand for the synthetic hexapeptide GH-releasing peptide (GHRP) and the putative hypophysiotropic factor pituitary adenylate cyclase-activating polypeptide (PA-CAP). Accordingly, we examined the effects of GHRP and PACAP on GH secretion at the single cell level using the reverse hemolytic plaque assay which allows distinction of effects on the number of secreting cells and the amount of hormone each cell secretes. Both factors stimulated GH secretion in a dose-dependent fashion, with PACAP being more effective. PACAP increased both the number of cells secreting and the mean amount of hormone secreted per cell. In contrast, GHRP increased the number of secreting cells, although it had no effect on the amount of secretion per cell. GH secretion induced by GHRH, GHRP, and PACAP was inhibited by SRIF, but the effect was predominantly on the number of cells secreting rather than the amount secreted per cell. Specific antagonists to GHRP and GHRH inhibited GH secretion induced by the respective agonist but not that induced by the other factor nor by PACAP. These findings confirm the complex nature of the regulation of GH secretion at the level of the somatotrope. At least three factors, operating via distinct receptors, are able to increase GH secretion. In addition, they ascribe a potential physiological role for the hitherto putative hypophysiotropic factor PACAP.
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PMID:Pituitary adenylate cyclase activating polypeptide, growth hormone (GH)-releasing peptide and GH-releasing hormone stimulate GH release through distinct pituitary receptors. 134 81

We recently reported isolation, characterization and synthesis of a novel ovine hypothalamic peptide with 38 residues which stimulates accumulation of cAMP in rat anterior pituitary cell cultures. The peptide was named PACAP38 (pituitary adenylate cyclase-activating polypeptide with 38 residues). The presence of another peptide corresponding to the N-terminal 1-27 residues (PACAP27) was also demonstrated. Both PACAP38 and PACAP27 have an amidated C-terminus. Antisera against synthetic PACAP27 were generated in rabbits. These antisera were tested for titer and specificity in enzyme-linked immunosorbent assay. One of the antisera (no. 88121-3) exhibited a high titer of antibody, which was specific to PACAP27 and PACAP38 with exception of slight cross-reactivity with ovine CRF (oCRF). Therefore, the antibodies against oCRF were removed from the antiserum using a solid phase method. Removal of oCRF antibodies was confirmed by enzyme-linked immunosorbent assay. A dense immunoreactive fiber network was found in both external and internal zones of the median eminence and pituitary stalk. The fibers were demonstrated to be in close contact with the hypophysial portal capillaries. The preabsorption of antiserum with vasoactive intestinal polypeptide or with the mixture containing TRH, LHRH, oCRF, ovine GH-releasing factor, somatostatin, and bovine thyroglobulin did not affect the immunostaining. On the other hand, the preabsorption of antiserum with an excess of PACAP27 or PACAP38 abolished the immunostaining. Therefore, the staining is considered specific for PACAP27 and PACAP38. Stained fibers were also present in the posterior pituitary. A dense fiber network was observed and the lateral hypothalamus the fibers appeared to cling to unstained neuronal cell bodies and their dendrites. In the lateral septum the fibers surrounded some blood vessels. Immunolabeled cell bodies were found in the paraventricular and supraoptic nuclei. These findings support the view that PACAP may play a multifunctional role, including that of a hypophysiotropic hormone, neurotransmitter, neuromodulator, and vasoregulator.
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PMID:Immunohistochemical demonstration of a novel hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide, in the ovine hypothalamus. 219 97

The novel 38-amino acid neuropeptide PACAP (pituitary adenylate activating peptide) has recently been shown to induce the pancreatic acinar tumour AR4-2J cell growth. This growth promoting effect of PACAP was, however, independent of adenylate cyclase activation but suppressed by pertussis toxin and the somatostatin analog SMS 201-995. This study was undertaken to search for potential cell signalling pathways involved in the growth promoting effect of PACAP on AR4-2J cells. The AR4-2J cells were grown in Dulbecco's Modified Eagle's Medium containing 10% foetal calf serum. For studies on cell signalling pathways, all experiments were carried out on cells which have reached 50 to 75% confluency. At that point, they were transferred to serum free medium overnight with or without 1 microCi/ml myristic acid. The next morning, cells were harvested, washed and used for tyrosine kinase and phospholipase D (PLD) activities. For studies on growth, cells were grown for 2 days in the presence of 1 nM PACAP +/- the different inhibitors of tyrosine kinase and PLD. PACAP-38 and -27 caused a dose-dependent and parallel activation of tyrosine kinase and PLD an effect prevented by the antagonist PACAP 7-38. PACAP-38-stimulated tyrosine kinase and PLD activation are both dose-dependently inhibited by SMS 201-995. Finally, PACAP-stimulated tyrosine kinase and PLD activities are both inhibited by cell's preincubation with genistein and pertussis toxin. After 2 days, the PACAP-induced increase in AR4-2J cell growth was significantly inhibited by increasing concentrations of genistein and wortmannin, inhibitors of tyrosine kinase, PLD and phosphatidylinositol 3-kinase, respectively. PACAP can induce concomitant activation of tyrosine kinase and PLD; this finding and the observation that inhibition of these two enzymes inhibited PACAP-induced AR4-2J cell growth strongly suggests that they are intimately involved in the overall process of PACAP-induced AR4-2J cell proliferation.
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PMID:Cell signalling pathway involved in PACAP-induced AR4-2J cell proliferation. 766 8

A binding assay for growth hormone releasing factor (GRF) has been developed using scintillation proximity assay (SPA) technology. Binding conditions were validated by several criteria. Equilibrium binding was attained within three hours at 22 degrees C in crude membrane fractions of HEK293 (293-P2) and GH4C1 (GH4-P1) cells transfected with the porcine GRF receptor. Saturation binding isotherms produced a KD of 296 pM and a Bmax of 4.7 pmols/mg membrane protein in 293-P2 cells. Cells not expressing the GRF receptor displayed no specific binding for the ligand. Competition binding curves produced the following rank order of potency for tested peptides: GRF analogs D-Ala2 = D-Arg2 (IC50 approximately 1 nM) >> PACAP > secretin, VIP (EC50 > 100 nM). Somatostatin (SRIF) binding was also adapted to the SPA format in a GH4C1 cell line transfected with the SRIF receptor subtype 2 (SSTR2) and in HEK293 cells transfected with the SRIF receptor subtype 5 (SSTR5). This assay represents a major improvement for binding measurements of these and potentially many other ligands for G-protein linked receptors, requiring no separation of bound from free hormone, allowing detailed pharmacological evaluations and enabling measurement of equilibrium binding in real time. In the 96-well format, it is suitable for high throughput screening.
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PMID:A rapid and sensitive binding assay for growth hormone releasing factor. 766 92

Pituitary adenylate cyclase activating polypeptide (PACAP38) stimulated growth hormone release as well as cAMP accumulation in a static rat primary pituitary cell culture in a dose-dependent manner with EC50 values of 1.9 +/- 0.4 nM (n = 13) and 0.9 +/- 0.3 nM (n = 5), respectively. The maximal GH response was observed between 5 to 15 min. Prolonged incubation (3 to 4 hrs) markedly reduced the stimulatory effect of PACAP38. The effect of PACAP38 on GH release was desensitized by pretreatment of the cells with PACAP38 or GRF, but not with PMA. The PACAP38-induced desensitization appeared to be time- and dose-dependent. Somatostatin (20 nM) inhibited PACAP-stimulated GH release through a cAMP-independent pathway.
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PMID:Pituitary adenylate cyclase activating polypeptide-induced desensitization on growth hormone release from rat primary pituitary cells. 790 58

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) stimulated GH secretion in superfused rat anterior pituitary cell in vitro and in conscious male rats in vivo. PACAP-38-induced GH secretion was inhibited by PACAP-(6-38), an N-terminal-deleted analog, at 100-fold concentrations of PACAP-38 both in vitro and in vivo. In contrast, a GH-releasing hormone antagonist did not affect the action of PACAP-38 to stimulate GH release in vitro. Plasma GH increase induced by i.v. injection of 5-hydroxy-L-tryptophan (1 mg/100 g BW), a precursor of serotonin, was blunted by PACAP-(6-38) (1 nmol/100 g BW, i.v.), whereas spontaneous pulsatile GH secretion in conscious male rats, which is governed by hypothalamic GH-releasing hormone and somatostatin, was not affected by repeated i.v. injection of PACAP-(6-36). These findings suggest that PACAP-(6-38) is a potent antagonist of PACAP-38 to stimulate GH secretion both in vivo and in vitro. Taken together with the facts that PACAP-38 is highly concentrated in the hypothalamus and that is released into the hypophysial portal blood, our present findings suggest that PACAP-38 might play a stimulatory role on GH secretion induced by serotoninergic mechanisms in the rat.
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PMID:Involvement of pituitary adenylate cyclase-activating polypeptide in growth hormone secretion induced by serotoninergic mechanisms in the rat. 861 3

Primary cultures of postganglionic sympathetic neurons were established more than 30 years ago. More recently, these cultures have been used to characterize various neurotransmitter receptors that govern sympathetic transmitter release. These receptors may be categorized into at least three groups: (1) receptors which evoke transmitter release: (2) receptors which facilitate; (3) receptors which inhibit, depolarization-evoked release. Group (1) comprises nicotinic and muscarinic acetylcholine receptors, P2X purinoceptors and pyrimidinoceptors. Group (2) currently harbours beta-adrenoceptors, P2 purinoceptors, receptors for PACAP and VIP, as well as prostanoid EP1 receptors. In group (3), muscarinic cholinoceptors, alpha 2- and beta-adrenoceptors, P2 purinoceptors, and receptors for the neuropeptides NPY, somatostatin (SRIF1) and LHRH, as well as opioid (delta and kappa) receptors can be found. Receptors which regulate transmitter release from neurons in cell culture may be located either at the somatodendritic region or at the sites of exocytosis, i.e. the presynaptic specializations of axons. Most of the receptors that evoke release are located at the soma. There ionotropic receptors cause depolarizations to generate action potentials which then trigger Ca(2+)-dependent exocytosis at axon terminals. The signalling mechanisms of metabotropic receptors which evoke release still remain to be identified. Receptors which facilitate depolarization-evoked release appear to be located preferentially at presynaptic sites and presumably act via an increase in cyclic AMP. Receptors which inhibit stimulation evoked release are also presynaptic origin and most commonly rely on a G protein-mediated blockade of voltage-gated Ca2+ channels. Results obtained with primary cell cultures of postganglionic sympathetic neurons have now supplemented previous data about neurotransmitter receptors involved in the regulation of ganglionic as well as sympatho-effector transmission. In the future, this technique may prove useful to identify yet unrecognized receptors which control the output of the sympathetic nervous system and to elucidate underlying signalling mechanisms.
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PMID:Receptors controlling transmitter release from sympathetic neurons in vitro. 908 89

Tissue specimens from the large bowel of 18 patients with long-standing slow transit constipation were investigated to determine the distribution and density of several neuropeptides and amines in the enteric nerve system, and also of endocrine cells in comparison to normal individuals. CGRP (calcitonin gene-related peptide), galanin, glucagon, GRP (gastrin-releasing peptide), metenkephalin, motilin, neuropeptide Y (NPY), PACAP, peptide YY (PYY), serotonin, somatostatin, substance P and VIP were studied by immunohistochemistry. Tissue concentrations of VIP, substance P and galanin were also measured by radioimmunoassay. Significantly increased VIP, SP and galanin contents were found in specimens from the ascending colon. Levels of VIP and galanin were also increased in the transverse colon. Immunohistochemistry revealed only marginal changes with an increased density of PACAP nerve fibres in the smooth muscle and of VIP and PACAP nerves in the myenteric plexus of the transverse colon. In the descending colon substance P and NPY immunoreactivity were also increased in the myenteric plexus while the density of VIP nerve fibres was reduced in the mucosa/submucosa. The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients.
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PMID:Neuropeptides in idiopathic chronic constipation (slow transit constipation). 934 69

1. Regulation of pulsatile secretion of growth hormone (GH) relies on hypothalamic neuronal loops, major transmitters involved in their operation are growth hormone releasing hormone (GHRH) synthetized mostly in arcuate nucleus (ARC) neurons, and somatostatin (SRIH), synthetized both in hypothalamus periventricular (PVe) and ARC neurons. 2. Neurons synthetizing both peptides can inhibit each other in a reciprocal manner. Other neuropeptides synthetized in ARC neurons, such as galanin, or in ARC interneurons, such as neuropeptide Y (NPY), are able to modulate synthesis and release of GHRH and SRIH into the hypothalamohypophyseal portal system. 3. In addition, the hitherto uncharacterized endogenous ligand of the recently cloned growth hormone releasing peptide receptor, expressed mostly in the ARC, triggers GH release, presumably by actions on ARC interneurons. 4. Thyroid, gonadal, and adrenal steroid hormones also affect the GHRH-SRIH balance; a differential distribution of sex steroid receptors in the ARC and the PVe is likely to account for the different pattern of GH secretion in male and female animals. 5. Growth hormone itself is able to inhibit the amplitude of GH secretory episodes and to increase their frequency, by entering the brain (presumably by receptor-mediated internalization at the level of the choroid plexus) and acting subsequently on ARC neurons. 6. At the pituitary level, major neurotransmitters regulating GH cells act on receptors of the VIP/PACAP/GHRH family and of the somatostatin family, in particular, sst2 and sst3. Those are coupled to accumulation of cAMP as a second messenger. 7. In addition, patch-clamp experiments and measurement of intracellular Ca2+ indicate that GH cells present characteristic, GHRH-dependent, but self-maintained Ca2+ spikes and [Ca2+]i transients, which reflect adaptive mechanisms to constraints of episodic release. 8. Recent data on transcription factors affecting GH gene expression and somatotrope differentiation are also summarized. 9. Regulation and differentiation of somatotropes also depend upon paracrine processes within the pituitary itself and involve growth factors and several neuropeptides, for instance, vasoactive intestinal peptide, angiotensin 2, endothelin, and activin. 10. Finally, characteristic changes occur in the GH secretory pattern under discrete, pathological conditions, such as abnormal growth and dwarfism, diabetes, and acromegaly, as well as during inflammatory processes.
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PMID:Hypothalamic and hypophyseal regulation of growth hormone secretion. 952 32

In the adenohypophysis, thyrotrophin-releasing hormone (TRH) is inactivated by pyroglutamyl peptidase II (PPII), a TRH-specific ectoenzyme localized in lactotrophs. TRH slowly downregulates surface PPII activity in adenohypophyseal cell cultures. Protein kinase C (PKC) activation mimics this effect. We tested the hypothesis that other hypothalamic factors controlling prolactin secretion could also regulate PPII activity in adenohypophyseal cell cultures. Incubation for 16 h with pituitary adenylate cyclase activator peptide 38 (PACAP; 10(-6) M) decreased PPII activity. Bromocryptine (10(-8) M), a D2 dopamine receptor agonist, or somatostatin (10(-6) M) stimulated enzyme activity and blocked the inhibitory effect of [3-Me-His2]-TRH, a TRH receptor agonist. Bromocryptine and somatostatin actions were suppressed by preincubation with pertussis toxin (400 ng ml(-1)). Because these hypophysiotropic factors transduce some of their effects using the cAMP pathway, we analysed its role on PPII regulation. Cholera toxin (400 ng ml(-1)) inhibited PPII activity. Forskolin (10(-6) M) caused a time-dependent decrease in PPII activity, with maximal inhibition at 12-16 h treatment; ED50 was 10(-7) M. 3-isobutyl-1-methylxanthine or dibutiryl cAMP, caused a dose-dependent inhibition of PPII activity. These data suggest that increased cAMP down-regulates PPII activity. The effect of PACAP was blocked by preincubation with H89 (10(-6) M), a protein kinase A inhibitor, suggesting that the cAMP pathway mediates some of the effects of PACAP. Maximal effects of forskolin and 12-O-tetradecanoylphorbol 13-acetate were additive. PPII activity, therefore, is independently regulated by the cAMP and PKC pathways. Because most treatments inhibited PPII mRNA levels similarly to PPII activity, an important level of control of PPII activity by these factors may be at the mRNA level. We suggest that PPII is subject to 'homologous' and 'heterologous' regulation by elements of the multifactorial system that controls prolactin secretion.
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PMID:Multiple hypothalamic factors regulate pyroglutamyl peptidase II in cultures of adenohypophyseal cells: role of the cAMP pathway. 957 8


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