Somatostatin binding capacity, guanylate cyclase and tyrosine phosphatase activities during pancreatic proliferation in the rat induced by gastrectomy

Rodrı́guez-Martı́n, Eulalia; Valencia, A.M.; Colás, Begoña; García-Escribano, Carmen; Rodrı́guez-Puyol, Manuel; Susini, C.; Arilla, E.

doi:10.1016/0196-9781(95)02023-3

Cited by 3 publications

(1 citation statement)

References 51 publications

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“…Somatostatin induces an increase of cGMP formation in CHO/sst2 cells as well as in mouse pancreatic acini. These data are in agreement with our previous results demonstrating a somatostatin-dependent activation of guanylate cyclase in rat pancreatic acinar membranes (46). Expression of an inactive SHP-1 in CHO/sst2 cells and in pancreatic acini derived from me v mice is associated with an absence of guanylate cyclase activation by somatostatin, whereas the exogenous NO donor SNP is still effective.…”

Section: Discussionsupporting

confidence: 93%

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

et al. 2001

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Somatostatin receptor sst2 is an inhibitory G protein-coupled receptor, which inhibits normal and tumor cell growth by a mechanism involving the tyrosine phosphatase SHP-1. We reported previously that SHP-1 associates transiently with and is activated by sst2 and is a critical component for sst2 growth inhibitory signaling. Here, we demonstrate that in Chinese hamster ovary cells expressing sst2, SHP-1 is associated at the basal level with the neuronal nitric oxide synthase (nNOS). Following sst2 activation by the somatostatin analog RC-160, SHP-1 rapidly recruits nNOS tyrosine dephosphorylates and activates it. The resulting NO activates guanylate cyclase and inhibits cell proliferation. Coexpression of a catalytically inactive SHP-1 mutant with sst2 blocks RC-160-induced nNOS dephosphorylation and activation, as well as guanylate cyclase activation. In mouse pancreatic acini, RC-160 treatment reduces nNOS tyrosine phosphorylation accompanied by an increase of its activity. By opposition, in acini from viable motheaten (mev/mev) mice, which express a markedly inactive SHP-1, RC-160 has no effect on nNOS activity. Finally, expression of a dominant-negative form of nNOS prevents both RC-160-induced p27 up-regulation and cell proliferation inhibition. We therefore identified nNOS as a novel SHP-1 substrate critical for sst2-induced cell-growth arrest.

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Section: Discussionsupporting

confidence: 93%

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

et al. 2001

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Somatostatin receptors

Møller

Stidsen

Hartmann

et al. 2003

Biochimica et Biophysica Acta (BBA) - Biomembranes

311

304

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In 1972, Brazeau et al. isolated somatostatin (somatotropin release-inhibiting factor, SRIF), a cyclic polypeptide with two biologically active isoforms (SRIF-14 and SRIF-28). This event prompted the successful quest for SRIF receptors. Then, nearly a quarter of a century later, it was announced that a neuropeptide, to be named cortistatin (CST), had been cloned, bearing strong resemblance to SRIF. Evidence of special CST receptors never emerged, however. CST rather competed with both SRIF isoforms for specific receptor binding. And binding to the known subtypes with affinities in the nanomolar range, it has therefore been acknowledged to be a third endogenous ligand at SRIF receptors. This review goes through mechanisms of signal transduction, pharmacology, and anatomical distribution of SRIF receptors. Structurally, SRIF receptors belong to the superfamily of G protein-coupled (GPC) receptors, sharing the characteristic seven-transmembrane-segment (STMS) topography. Years of intensive research have resulted in cloning of five receptor subtypes (sst(1)-sst(5)), one of which is represented by two splice variants (sst(2A) and sst(2B)). The individual subtypes, functionally coupled to the effectors of signal transduction, are differentially expressed throughout the mammalian organism, with corresponding differences in physiological impact. It is evident that receptor function, from a physiological point of view, cannot simply be reduced to the accumulated operations of individual receptors. Far from being isolated functional units, receptors co-operate. The total receptor apparatus of individual cell types is composed of different-ligand receptors (e.g. SRIF and non-SRIF receptors) and co-expressed receptor subtypes (e.g. sst(2) and sst(5) receptors) in characteristic proportions. In other words, levels of individual receptor subtypes are highly cell-specific and vary with the co-expression of different-ligand receptors. However, the question is how to quantify the relative contributions of individual receptor subtypes to the integration of transduced signals, ultimately the result of collective receptor activity. The generation of knock-out (KO) mice, intended as a means to define the contributions made by individual receptor subtypes, necessarily marks but an approximation. Furthermore, we must now take into account the stunning complexity of receptor co-operation indicated by the observation of receptor homo- and heterodimerisation, let alone oligomerisation. Theoretically, this phenomenon adds a novel series of functional megareceptors/super-receptors, with varied pharmacological profiles, to the catalogue of monomeric receptor subtypes isolated and cloned in the past. SRIF analogues include both peptides and non-peptides, receptor agonists and antagonists. Relatively long half lives, as compared to those of the endogenous ligands, have been paramount from the outset. Motivated by theoretical puzzles or the shortcomings of present-day diagnostics and therapy, investigators have also aimed to produce subtype-sel...

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Endoplasmic reticulum Ca²⁺-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells

Gukovskaya

Gukovsky

Pandol

2000

American Journal of Physiology-Cell Physiology

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In this study, we show that particulate guanylate cyclase (GC) is present in rat pancreatic acinar cells and is located both on plasma membrane and membranes of endoplasmic reticulum (ER). Western blot analysis indicates that the enzyme isoform GC-A is present in the acinar cell membranes. The specific inhibitors of ER Ca(2+)-ATPase thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), and cyclopiazonic acid all activated particulate GC in pancreatic acini, both in membrane fractions and intact cells. These inhibitors also induced dephosphorylation of GC. Dose dependencies of Ca(2+)-ATPase inhibition and GC activation by BHQ are very similar, and those for thapsigargin partially overlap. ER Ca(2+)-ATPase and GC are coimmunoprecipitated both by antisera against membrane GC and by antisera against ER Ca(2+)-ATPase, suggesting a physical association between the two enzymes. The results suggest that thapsigargin and the other inhibitors act through ER Ca(2+)-ATPase to activate membrane GC in pancreatic acinar cells, although their direct effect on GC cannot be excluded.

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Somatostatin binding capacity, guanylate cyclase and tyrosine phosphatase activities during pancreatic proliferation in the rat induced by gastrectomy

Cited by 3 publications

References 51 publications

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

Somatostatin receptors

Endoplasmic reticulum Ca²⁺-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells

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Somatostatin binding capacity, guanylate cyclase and tyrosine phosphatase activities during pancreatic proliferation in the rat induced by gastrectomy

Cited by 3 publications

References 51 publications

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

Neuronal nitric oxide synthase is a SHP‐1 substrate involved in sst2 somatostatin receptor growth inhibitory signaling

Somatostatin receptors

Endoplasmic reticulum Ca2+-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells

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Endoplasmic reticulum Ca²⁺-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells