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Victor Sanchezmargalet - One of the best experts on this subject based on the ideXlab platform.
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reprint of metabolic effects and mechanism of action of the chromogranin a derived peptide Pancreastatin
Regulatory Peptides, 2010Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad Najib, Jose SantosalvarezAbstract:Abstract Pancreastatin is one of the regulatory peptides derived from intracellular and/or extracellular processing of chromogranin A, the soluble acidic protein present in the secretory granules of the neuroendocrine system. While the intracellular functions of chromogranin A include formation and maturation of the secretory granule, the major extracellular functions are generation of biologically active peptides with demonstrated autocrine, paracrine or endocrine activities. In this review, we will focus on the metabolic function of one of these peptides, Pancreastatin, and the mechanisms underlying its effects. Many different reported effects have implicated PST in the modulation of energy metabolism, with a general counterregulatory effect to that of insulin. Pancreastatin induces glycogenolysis in liver and lipolysis in adipocytes. Metabolic effects have been confirmed in humans. Moreover, naturally occurring human variants have been found, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. Thus, qualitative hereditary alterations in Pancreastatin's primary structure may give rise to interindividual differences in glucose and lipid metabolism. Pancreastatin activates a receptor signaling system that belongs to the seven-spanning transmembrane receptor coupled to a Gq–PLCβ–calcium–PKC signaling pathway. Increased Pancreastatin plasma levels, correlating with catecholamines levels, have been found in insulin resistance states, such as gestational diabetes or essential hypertension. Pancreastatin plays important physiological role in potentiating the metabolic effects of catecholamines, and may also play a pathophysiological role in insulin resistance states with increased sympathetic activity.
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metabolic effects and mechanism of action of the chromogranin a derived peptide Pancreastatin
Regulatory Peptides, 2010Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad Najib, Jose SantosalvarezAbstract:Abstract Pancreastatin is one of the regulatory peptides derived from intracellular and/or extracellular processing of chromogranin A, the soluble acidic protein present in the secretory granules of the neuroendocrine system. While the intracellular functions of chromogranin A include formation and maturation of the secretory granule, the major extracellular functions are generation of biologically active peptides with demonstrated autocrine, paracrine or endocrine activities. In this review, we will focus on the metabolic function of one of these peptides, Pancreastatin, and the mechanisms underlying its effects. Many different reported effects have implicated PST in the modulation of energy metabolism, with a general counterregulatory effect to that of insulin. Pancreastatin induces glycogenolysis in liver and lipolysis in adipocytes. Metabolic effects have been confirmed in humans. Moreover, naturally occurring human variants have been found, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. Thus, qualitative hereditary alterations in Pancreastatin's primary structure may give rise to interindividual differences in glucose and lipid metabolism. Pancreastatin activates a receptor signaling system that belongs to the seven-spanning transmembrane receptor coupled to a Gq–PLCβ–calcium–PKC signaling pathway. Increased Pancreastatin plasma levels, correlating with catecholamines levels, have been found in insulin resistance states, such as gestational diabetes or essential hypertension. Pancreastatin plays important physiological role in potentiating the metabolic effects of catecholamines, and may also play a pathophysiological role in insulin resistance states with increased sympathetic activity.
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Pancreastatin a chromogranin a derived peptide inhibits dna and protein synthesis by producing nitric oxide in htc rat hepatoma cells
Journal of Hepatology, 2001Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Souad NajibAbstract:Abstract Background/Aims : Pancreastatin, a chromogranin A-derived peptide, has a counter-regulatory effect on insulin action. We have previously characterized Pancreastatin receptor and signalling in rat liver and HTC hepatoma cells. A G α q/11 -PLC- β pathway leads to an increase in [Ca 2+ ] i , PKC and mitogen activated protein kinase (MAPK) activation. These data suggested that Pancreastatin might have a role in growth and proliferation, similar to other calcium-mobilizing hormones. Methods : DNA and protein synthesis were measured as [ 3 H]-thymidine and [ 3 H]-leucine incorporation. Nitric oxide (NO) was determined by the Griess method and cGMP production was quantified by enzyme-linked immunoassay. Results : Contrary to the expected results, we have found that Pancreastatin inhibits protein and DNA synthesis in HTC hepatoma cells. On the other hand, when the activity of NO synthase was inhibited by N -monomethyl- l -arginine (NMLA), the inhibitory effect of Pancreastatin on DNA and protein synthesis was not only reverted, but a dose-dependent stimulatory effect was observed, probably due to MAPK activation, since it was prevented by PD98059. These data strongly suggested the role of NO in the inhibitory effect of Pancreastatin on protein and DNA synthesis, which is overcoming the effect on MAPK activation. Moreover, Pancreastatin dose-dependently increased NO production in parallel to cyclic guanosine monophosphate (cGMP). Both effects were prevented by NMLA. Finally, an indirect effect of Pancreastatin through the induction of apoptosis was ruled out. Conclusions : Therefore, the NO and the cGMP produced by the NO-activated guanylate cyclase may mediate the dose-dependent inhibitory effect of Pancreastatin on growth and proliferation in HTC hepatoma cells.
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characterization of Pancreastatin receptor and signaling in rat htc hepatoma cells
European Journal of Pharmacology, 2000Co-Authors: Victor Sanchezmargalet, Carmen Gonzalezyanes, Jose Santosalvarez, Souad NajibAbstract:Abstract Pancreastatin, a chromogranin A-derived peptide widely distributed throughout the neuroendocrine system, has a general inhibitory effect on endocrine secretion and a counterregulatory effect on insulin action. We have recently described the cross-talk of Pancreastatin with insulin signaling in rat hepatoma cells (HTC), where it inhibits insulin action and signaling through the serine phosphorylation of the insulin receptor, thereby impairing tyrosine kinase activity. Here, we have characterized Pancreastatin receptors and signaling in HTC cells. The Pancreastatin effector systems were studied by determining phospholipase C activity in HTC membranes and mitogen-activated protein kinase (MAPK) phosphorylation activity in HTC cells. Binding studies with radiolabeled Pancreastatin showed a population of high affinity binding sites, with a B max of 8 fmol/mg protein and a K d of 0.6 nM. Moreover, we assessed the coupling of the receptor with a G protein system by inhibiting the binding with guanine nucleotide and by measuring the GTP binding to HTC membranes. We found that Pancreastatin receptor was coupled with a Gα q/11 protein which activates phospholipase C-β 1 and phospholipase C-β 3 , in addition to MAPK via both βγ and α q/11 .
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affinity purification of Pancreastatin receptor gq 11 protein complex from rat liver membranes
Archives of Biochemistry and Biophysics, 2000Co-Authors: Jose Santosalvarez, Victor SanchezmargaletAbstract:Abstract Pancreastatin, a chromogranin A derived peptide, exerts a glycogenolytic effect on the hepatocyte. This effect is initiated by binding to membrane receptors which are coupled to pertussis toxin insensitive G proteins belonging to the Gq/11 family. We have recently solubilized active Pancreastatin receptors from rat liver membranes still functionally coupled to G proteins. Here, we have purified Pancreastatin receptors by a two-step procedure. First, Pancreastatin receptors with their associated Gq/11 regulatory proteins were purified from liver membranes by lectin absorption chromatography on wheat germ agglutinin immobilized on agarose. A biotinylated rat Pancreastatin analog was tested for binding to liver membranes before using it for affinity purification. Unlabeled biotinylated rat Pancreastatin competed for 125 I-labeled [Tyr 0 ]PST binding to solubilized receptors with a K d = 0.27 nM, comparable to that of native Pancreastatin. The biotinylated analog was immobilized on streptavidin-coated Sepharose beads and used to further affinity purify wheat germ agglutinin eluted receptor material. Specific elution at low pH showed that the receptor protein was purified as an 80-kDa protein in association with a G protein of the q/11 family, as demonstrated by specific immunoblot analysis. The specificity of the receptor band was assessed by chemical cross-linking of the purified material followed by SDS–PAGE and autoradiography. In conclusion, we have purified Pancreastatin receptor as a glycoprotein of 80 kDa physically associated with a Gq/11 protein.
R Goberna - One of the best experts on this subject based on the ideXlab platform.
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increased plasma Pancreastatin like levels in gestational diabetes correlation with catecholamine levels
Diabetes Care, 1998Co-Authors: Victor Sanchezmargalet, J A Lobon, Fernando Escobarjimenez, Amalia Gonzalez, M L Fernandezsoto, R GobernaAbstract:OBJECTIVE: To investigate plasma Pancreastatin (a chromogranin A-derived peptide) and catecholamine levels (counterregulatory hormones) in subjects with gestational diabetes compared with normal pregnant subjects. RESEARCH DESIGN AND METHODS: Fasting blood samples were obtained from 11 normal pregnant and 12 nonobese gestational diabetic subjects at late pregnancy (30+/-1 weeks). Selection criteria were those recommended by the National Diabetes Data Group (modified from O'Sullivan original criteria). Plasma glucose, insulin, glucagon, Pancreastatin-like, epinephrine, and norepinephrine were measured. RESULTS: Gestational diabetic subjects had significantly higher insulin levels than control pregnant subjects (18+/-1 vs. 15+/-1 microU/ml), whereas glucose and glucagon levels where comparable in the two groups. However, increased catecholamine levels (epinephrine and norepinephrine) were found in the gestational diabetic group. We also found increased Pancreastatin-like levels in these patients compared with the pregnant control group (46+/-2 vs. 30+/-2 pmol/l). Actually, Pancreastatin levels positively correlated with both epinephrine (r = 0.34) and norepinephrine (r = 0.80) levels. CONCLUSIONS: Catecholamine and Pancreastatin-like levels were found elevated in gestational diabetic subjects. These counterregulatory hormones may play a role in the insulin resistance syndrome of gestational diabetes.
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Pancreastatin further evidence for its consideration as a regulatory peptide
Journal of Molecular Endocrinology, 1996Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:: Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield Pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed Pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of Pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that Pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter-regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of Pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of Pancreastatin and thus to clarify its physiological role in the neuroendocrine system.
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Pancreastatin action in the liver dual coupling to different g proteins
Cellular Signalling, 1996Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:Abstract Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from porcine pancreas. Its biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A, which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. We have been interested in Pancreastatin action in the liver. We found that Pancreastatin has a glycogenolytic effect in the hepatocyte both in vivo and in vitro. We then studied and characterized the specific Pancreastatin receptor in the rat liver plasma membrane, as well as the specific signal transduction. This receptor appears to be coupled to two different G proteins. A pertussis toxin-insensitive G proteins leads to the activation of phospholipase C, and therefore mediates the glycogenolytic effect in the liver by increasing cytoplasmic free calcium and stimulating protein kinase C. The role of cyclic GMP in the action of Pancreastatin is not known yet, although it seems to regulate negatively the activation of phospholipase C. The precise mechanism by which Pancreastatin stimulates quanylate cyclase activity remains to be studied.
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increased plasma Pancreastatin like immunoreactivity levels in non obese patients with essential hypertension
Journal of Hypertension, 1995Co-Authors: M Valle, J A Lobon, A Maldonado, Fernando Escobarjimenez, J Olivan, R Perezcano, R GobernaAbstract:DESIGN: Pancreastatin, a novel peptide, is known to inhibit insulin secretion and to have a glycogenolytic effect, and is present in many endocrine and chromaffin cells. Both the plasma insulin levels and the adrenergic activity accompanying insulin resistance have been shown to be increased in hypertensive subjects. Our working hypothesis was that Pancreastatin might play a role in these pathological phenomena. METHODS: We studied the plasma Pancreastatin level in non-obese essential hypertensive patients in response to an intravenous glucose load. We further measured the responses to the glucose challenge of insulin, glucagon, catecholamines and free fatty acids, as well as other factors related to insulin resistance (i.e. lipoproteins and apolipoproteins). We separated the hypertensive patients into three groups according to their response to an oral glucose-tolerance test: normoinsulinaemic, hyperinsulinaemic and glucose-intolerant. Matched normotensive control subjects were also studied. RESULTS: Pancreastatin levels did not change in the control group after the glucose challenge. However, all hypertensive patients showed an increase in plasma Pancreastatin levels after glucose loading. The normoinsulinaemic hypertensive patients also had elevated basal Pancreastatin levels. The increase in Pancreastatin levels was in the ranking: normoinsulinaemic > hyperinsulinaemic > glucose-intolerant. The Pancreastatin: insulin ratio showed that the secretion of Pancreastatin and insulin may be regulated differently. Basal free fatty acid and glucagon levels were found to be elevated both in the hyperinsulinaemic and in the glucose-intolerant group. Fasting triglycerides levels were increased in all of the hypertensive patients. Other risk factors for coronary artery disease were also found to be altered: elevated very low-density lipoprotein-cholesterol and decreased high-density lipoprotein-cholesterol, with ranking: normoinsulinaemic < hyperinsulinaemic < glucose-intolerant. CONCLUSIONS: These results show an increase in Pancreastatin levels in hypertensive patients, suggesting that Pancreastatin might play a role in the pathophysiology of essential hypertension.
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Pancreastatin activates protein kinase c by stimulating the formation of 1 2 diacylglycerol in rat hepatocytes
Biochemical Journal, 1994Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:We describe here the stimulation by Pancreastatin of 1,2-diacylglycerol production and protein kinase C activity in liver plasma membrane and isolated hepatocytes. The dose-dependency for the stimulation of both processes was similar to the recently described pattern of glucose output and cytosolic Ca2+ transients produced by Pancreastatin. The time course of diacylglycerol production at 30 degrees C showed a rapid increase within 5 min, reaching a maximum at 10 min. Protein kinase C from hepatocytes was dependent on Ca2+ and phosphatidylserine. Neither the Pancreastatin-stimulated diacylglycerol production nor the activation of protein kinase C was affected by pretreatment with pertussis toxin. However, the presence of GTP partially inhibited this Pancreastatin stimulation of 1,2-diacylglycerol in a dose-dependent manner, although GTP alone stimulates diacylglycerol accumulation. This inhibitory effect of GTP on Pancreastatin stimulation of diacylglycerol synthesis was completely abolished by the pretreatment with pertussis toxin. In conclusion, this study provides evidence that Pancreastatin stimulates the formation of 1,2-diacylglycerol by a pertussis-toxin-independent mechanism, which may be responsible for the Pancreastatin activation of protein kinase C.
J E S Ardill - One of the best experts on this subject based on the ideXlab platform.
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A rapid rise in circulating Pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours.
Annals of clinical biochemistry, 2008Co-Authors: R L Stronge, G B Turner, B T Johnston, D R Mccance, A Mcginty, C C Patterson, J E S ArdillAbstract:To assess the value of Pancreastatin as a predictive factor for identifying patients with neuroendocrine tumours (NETs) who respond poorly to somatostatin analogues. A retrospective study of patients with NETs. Patient records from the Northern Ireland Neuroendocrine Tumour Register were interrogated. Those who had Pancreastatin concentrations measured on two or more occasions, before and during somatostatin analogue therapy (within the set time-limits) were selected. Data relating to diagnosis, surgery, somatostatin analogue therapy and survival outcome were noted. Data were subjected to univariate and multivariate analysis using Cox proportional hazard model. Fifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in Pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical prognostic indicators were: tumour location (P < 0.001), pre-treatment Pancreastatin (P < 0.001) and Pancreastatin change (P < 0.001). This study endorses the finding that Pancreastatin is a useful prognostic indicator of neuroendocrine disease. On commencement of treatment, one-third of the subjects showed an immediate negative Pancreastatin response to somatostatin analogues, which was associated with poor survival. This is the first study to document such an association. These findings have significant therapeutic consequences. In the presence of a rapidly rising Pancreastatin alternative, treatment modalities should be sought.
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a rapid rise in circulating Pancreastatin in response to somatostatin analogue therapy is associated with poor survival in patients with neuroendocrine tumours
Annals of Clinical Biochemistry, 2008Co-Authors: R L Stronge, G B Turner, B T Johnston, D R Mccance, A Mcginty, Christopher Patterson, J E S ArdillAbstract:AimTo assess the value of Pancreastatin as a predictive factor for identifying patients with neuroendocrine tumours (NETs) who respond poorly to somatostatin analogues.MethodsA retrospective study of patients with NETs. Patient records from the Northern Ireland Neuroendocrine Tumour Register were interrogated. Those who had Pancreastatin concentrations measured on two or more occasions, before and during somatostatin analogue therapy (within the set time-limits) were selected. Data relating to diagnosis, surgery, somatostatin analogue therapy and survival outcome were noted. Data were subjected to univariate and multivariate analysis using Cox proportional hazard model.ResultsFifty-nine patients with gastroenteropancreatic NETs fulfilled the inclusion criteria. Factors associated with a poor survival outcome on univariate analysis were primary tumour site (P = 0.006) and rapid rise in Pancreastatin during somatostatin analogue treatment (P < 0.001). In multivariate analysis, highly significant clinical pr...
Miguel Lucas - One of the best experts on this subject based on the ideXlab platform.
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Pancreastatin further evidence for its consideration as a regulatory peptide
Journal of Molecular Endocrinology, 1996Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:: Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from the porcine pancreas, and whose biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A (CGA), which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. Both intracellular and extracellular processing of CGA can yield Pancreastatin. This processing is tissue-specific, with the pancreatic islet and antral gastric endocrine cells being the major source of fully processed Pancreastatin. Most of the circulating CGA is secreted by chromaffin tissue. Therefore, peripheral processing of CGA is probably the major indirect source of Pancreastatin. Pancreastatin seems to have a general modulatory control on endocrine (insulin, glucagon, parathormone) and exocrine (pancreatic, gastric) secretion from tissues close to the source of production. This has led to the assumption that Pancreastatin may be a peptide with an autocrine and paracrine function. It has recently been revealed to be a peptide with a metabolic function counter-regulatory to insulin action. This effect, in conjunction with the inhibitory effect on insulin and pancreatic exocrine secretion, points to a role in the physiology of stress. The molecular mechanism of the glycogenolytic effect of Pancreastatin is better known, although further work is still needed. In general, more studies should be carried out at the molecular level to investigate the mechanism of action of Pancreastatin and thus to clarify its physiological role in the neuroendocrine system.
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Pancreastatin action in the liver dual coupling to different g proteins
Cellular Signalling, 1996Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:Abstract Pancreastatin is a 49 amino acid peptide first isolated, purified and characterized from porcine pancreas. Its biological activity in different tissues can be assigned to the C-terminal part of the molecule. Pancreastatin has a prohormonal precursor, chromogranin A, which is a glycoprotein present in neuroendocrine cells, including the endocrine pancreas. We have been interested in Pancreastatin action in the liver. We found that Pancreastatin has a glycogenolytic effect in the hepatocyte both in vivo and in vitro. We then studied and characterized the specific Pancreastatin receptor in the rat liver plasma membrane, as well as the specific signal transduction. This receptor appears to be coupled to two different G proteins. A pertussis toxin-insensitive G proteins leads to the activation of phospholipase C, and therefore mediates the glycogenolytic effect in the liver by increasing cytoplasmic free calcium and stimulating protein kinase C. The role of cyclic GMP in the action of Pancreastatin is not known yet, although it seems to regulate negatively the activation of phospholipase C. The precise mechanism by which Pancreastatin stimulates quanylate cyclase activity remains to be studied.
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Pancreastatin activates protein kinase c by stimulating the formation of 1 2 diacylglycerol in rat hepatocytes
Biochemical Journal, 1994Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:We describe here the stimulation by Pancreastatin of 1,2-diacylglycerol production and protein kinase C activity in liver plasma membrane and isolated hepatocytes. The dose-dependency for the stimulation of both processes was similar to the recently described pattern of glucose output and cytosolic Ca2+ transients produced by Pancreastatin. The time course of diacylglycerol production at 30 degrees C showed a rapid increase within 5 min, reaching a maximum at 10 min. Protein kinase C from hepatocytes was dependent on Ca2+ and phosphatidylserine. Neither the Pancreastatin-stimulated diacylglycerol production nor the activation of protein kinase C was affected by pretreatment with pertussis toxin. However, the presence of GTP partially inhibited this Pancreastatin stimulation of 1,2-diacylglycerol in a dose-dependent manner, although GTP alone stimulates diacylglycerol accumulation. This inhibitory effect of GTP on Pancreastatin stimulation of diacylglycerol synthesis was completely abolished by the pretreatment with pertussis toxin. In conclusion, this study provides evidence that Pancreastatin stimulates the formation of 1,2-diacylglycerol by a pertussis-toxin-independent mechanism, which may be responsible for the Pancreastatin activation of protein kinase C.
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Pancreastatin increases free cytosolic ca2 in rat hepatocytes involving both pertussis toxin sensitive and insensitive mechanisms
Biochemical Journal, 1993Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:Freshly isolated rat hepatocytes, loaded with the Ca2+ probe Fluo-3, responded to homologous Pancreastatin with a sudden increase in free cytosolic Ca2+ ([Ca2+]i) as well as glucose release. Addition of rat Pancreastatin (0.1 microM) to hepatocytes resulted in an increase in [Ca2+]i from 150 nM to 700 nM, which declined back to nearly basal values within 2-3 min. Half-maximal and maximal effects were observed at 0.3 and 100 nM Pancreastatin respectively. The increase in [Ca2+]i induced by vasopressin and noradrenaline was very similar in extent (from 150 to 800 nM) to that produced by Pancreastatin. Neither the alpha 1-adrenergic blocker prazosin nor the vasopressin antagonist V1 modified the increase in [Ca2+]i induced by Pancreastatin. Pig Pancreastatin and its 33-49 C-terminal fragment produced about 65 and 75% of the effect of homologous Pancreastatin respectively. Glucose production correlated with changes in [Ca2+]i in the same order of potency: vasopressin > rat Pancreastatin > pig 33-49 Pancreastatin > pig 1-49 Pancreastatin. The effect of Pancreastatin on [Ca2+]i was decreased by 50% when Ca2+ was omitted from the medium, and totally abolished when hepatocytes were depleted of internal Ca2+ stores by preincubation without Ca2+ and with 2 mM EGTA. When hepatocytes were preincubated for 5 min with PMA, the effects of ATP and noradrenaline were prevented, and those of vasopressin and Pancreastatin remained unchanged. The pretreatment of hepatocytes with pertussis toxin diminished the response to Pancreastatin and vasopressin. These results suggest that Pancreastatin is a new Ca(2+)-mobilizing glycogenolytic hormone acting through a specific receptor which may involve both pertussis-toxin-sensitive and -insensitive GTP-binding regulatory proteins.
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Pancreastatin increases cytosolic ca2 in insulin secreting rinm5f cells
Molecular and Cellular Endocrinology, 1992Co-Authors: Victor Sanchezmargalet, Miguel Lucas, R GobernaAbstract:Abstract We have investigated the effect of Pancreastatin on cytosolic Ca 2+ concentration in the insulin secreting cell line RINm5F. Changes in [Ca 2+ ] i induced by Pancreastatin were detected by Fluo-3 fluorescence using both flow cytometry and batch analysis measurements, and turned out to be from 90 to 315 nM equivalent to 80% of that caused by ATP, which increased [Ca 2+ ] i from 90 nM to 400 nM. This effect of Pancreastatin did not depend on extracellular calcium and was not mediated by α-adrenergic receptors since it was not prevented by the α-blocker yohimbine. It is concluded that Pancreastatin has a role in the homeostasis of free cytosolic calcium in the insulin secreting cell line Rinm5F.
R Hakanson - One of the best experts on this subject based on the ideXlab platform.
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histamine depletion does not affect Pancreastatin secretion from isolated rat stomach ecl cells
European Journal of Pharmacology, 2000Co-Authors: Erik Lindstrom, Per Norlen, R HakansonAbstract:Abstract ECL cells co-secrete histamine and Pancreastatin, a chromogranin A-derived peptide, in response to gastrin. The aim of the study was to explore possible ways to deplete ECL cells of histamine without affecting Pancreastatin and to examine how histamine depletion affects Pancreastatin secretion. Isolated rat stomach ECL cells (80–85% purity), prepared by counter-flow elutriation, were cultured for 48 h in the presence of α-fluoromethylhistidine (histidine decarboxylase inhibitor), bafilomycin A 1 (inhibitor of vacuolar-type proton-translocating ATPase) or reserpine (inhibitor of vesicular monoamine transporter). At this stage, the cells were challenged with 10 nM (EC 100 ) gastrin-17 for 30 min. Histamine and Pancreastatin were determined by radioimmunoassay. Maximally effective concentrations of α-fluoromethylhistidine, bafilomycin A 1 and reserpine were found to lower ECL-cell histamine (by 60%, 78% and 80%, respectively) without affecting Pancreastatin. Basal histamine secretion was reduced in a dose-dependent manner by all three drugs. Gastrin-evoked histamine secretion was reduced greatly by the three agents, while Pancreastatin secretion was unaffected. The results show that histamine can be depleted not only by inhibiting its formation (α-fluoromethylhistidine), but also (and more effectively) by inhibiting histamine vesicular uptake, directly (reserpine) or indirectly (bafilomycin A 1 ). The results also indicate that although histamine is co-stored with Pancreastatin, it is not required for either storage or secretion of Pancreastatin.
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expression of the chromogranin a derived peptides Pancreastatin and we14 in rat stomach ecl cells
Regulatory Peptides, 1997Co-Authors: Per Norlen, Duan Chen, Chunmei Zhao, W J Curry, C F Johnston, R HakansonAbstract:Abstract The ECL cells constitute the predominant endocrine cell population in the mucosa of the acid-secreting part of the stomach (fundus). They are rich in chromogranin A (CGA), histamine and histidine decarboxylase (HDC). They secrete CGA-derived peptides and histamine in response to gastrin. The objective of this investigation was to examine the expression of Pancreastatin (rat CGA 266-314 ) and WE 14 (rat CGA 343-356 ) in rat stomach ECL cells. The distribution and cellular localisation of Pancreastatin- and WE 14 -like immunoreactivities (LI) were analysed by radioimmunoassay and immunohistochemistry with antibodies against Pancreastatin, WE 14 and HDC. The effect of food deprivation on circulating Pancreastatin-LI was examined in intact rats and after gastrectomy or fundectomy. Rats received gastrin-17 (5 nmol/kg/h) by continuous intravenous infusion or omeprazole (400 μmol/kg) once daily by the oral route, to induce hypergastrinemia. CGA-derived peptides in the ECL cells were characterised by gel permeation chromatography. The expression of CGA mRNA was examined by Northern blot analysis. Among all of the endocrine cells in the body, the ECL cell population was the richest in Pancreastatin-LI, containing 20–25% of the total body content. Food deprivation and/or surgical removal of the ECL cells lowered the level of Pancreastatin-LI in serum by about 80%. Activation of the ECL cells by gastrin infusion or omeprazole treatment raised the serum level of Pancreastatin-LI, lowered the concentrations of Pancreastatin- and WE 14 -LI in the ECL cells and increased the CGA mRNA concentration. Chromatographic analysis of the various CGA immunoreactive components in the ECL cells of normal and hypergastrinemic rats suggested that these cells respond to gastrin with a preferential release of the low-molecular-mass forms.
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evidence that rat stomach ecl cells represent the main source of circulating Pancreastatin
Regulatory Peptides, 1997Co-Authors: Keizo Kimura, Duan Chen, Erik Lindstrom, Chunmei Zhao, R HakansonAbstract:Abstract Recently, we showed that the ECL cells in the oxyntic mucosa of the rat stomach are an important source of circulating Pancreastatin, a fragment of chromogranin A. The present study examined how much the ECL cells contribute to the circulating levels of Pancreastatin during omeprazole-evoked hypergastrinemia. Rats received omeprazole (400 μmol kg−1 day−1) by the oral route for 3 weeks. Two weeks after the start of the treatment, the rats were subjected to a sham operation or fundectomy. The concentrations of gastrin and Pancreastatin in serum were monitored before and after the operations. The ECL cells were visualized by Pancreastatin immunostaining and their number was determined. The activity of oxyntic mucosal histidine decarboxylase (HDC) was measured before and after 2 weeks of omeprazole treatment. Omeprazole-induced hypergastrinemia resulted in elevated serum Pancreastatin and increased oxyntic mucosal HDC activity. Pancreastatin-immunoreactive cells were equally numerous before and after 2 weeks of omeprazole treatment. After surgical removal of the ECL cells by fundectomy, the serum gastrin concentration remained high whereas the serum Pancreastatin concentration decreased by 90%. We conclude that the ECL cells in omeprazole-treated rats are responsible for 90% of circulating Pancreastatin.
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gastrin evoked secretion of Pancreastatin and histamine from ecl cells and of acid from parietal cells in isolated vascularly perfused rat stomach effects of isobutyl methylxanthin and α fluoromethylhistidine
Regulatory Peptides, 1996Co-Authors: Duan Chen, Ronald Marvik, Kirsten Ronning, Kjell Andersson, Helge L Waldum, R HakansonAbstract:Abstract The ECL cells in the rat stomach release Pancreastatin and histamine in response to gastrin stimulation. The present study compares the release of Pancreastatin and histamine from the ECL cells and the secretion of acid from the parietal cells in response to gastrin, and examines how a markedly reduced histamine content in the ECL cells will affect the gastrin-evoked release of Pancreastatin and the secretion of gastric acid. Totally isolated, vascularly perfused stomachs were prepared from fasted rats. Some of the rats had been pre-treated for 24 h with (α-fluoromethylhistidine (α-FMH), resulting in 80% depletion of oxyntic mucosal histamine (mainly ECL-cell histamine). The stomachs were perfused with rat gastrin-17, α-FMH, isobutyl methylxanthine (IBMX), or vehicle in various combinations for 8 h. The venous outflow was collected (30-min samples) for determination of histamine and Pancreastatin-like immunoreactivity (LI) and the gastric luminal outflow was collected for determination of H + . Gastrin raised the outflow of Pancreastatin-LI and histamine but did not raise the acid output unless IBMX was added. The outflow of Pancreastatin-LI and histamine was greater after gastrin + IBMX (at least during the first 4-h period) than after gastrin alone. α-FMH reduced gastrin-evoked histamine outflow but did not affect gastrin-evoked Pancreastatin-LI outflow. Also the acid output in response to gastrin + IBMX was much reduced by α-FMH. In conclusion, increased levels of intracellular cAMP enhanced the gastrin-evoked release of Pancreastatin-LI and histamine from the ECL cells and made it possible for histamine, released from the ECL cells, to cause acid secretion from the parietal cells. ECL-cell histamine depletion reduced the gastrin-evoked acid secretion; it did not affect the gastrin-evoked release of Pancreastatin-LI.
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circulating Pancreastatin is a marker for the enterochromaffin like cells of the rat stomach
Gastroenterology, 1995Co-Authors: R Hakanson, Per Norlen, Xiqin Ding, Duan ChenAbstract:Abstract Background/Aims Peptides of the chromogranin family occur in peptide hormone—producing cells throughout the body. One source of such peptides is the enterochromaffin-like (ECL) cells, which constitute the predominant population of endocrine cells in the fundus (the acid-producing part) of the rat stomach. The purpose of this study was to examine whether ECL cells, which are controlled by gastrin, represent a major source of circulating Pancreastatin, a fragment of chromogranin A. Methods Rats underwent surgical procedures and treatments in which the ECL cells could be manipulated. The procedures included antrectomy, fundectomy, and gastrectomy (and adrenalectomy), and the treatments included fasting or feeding, gastrin-17 infusion, and administration of omeprazole or ranitidine. The concentrations of Pancreastatin-like immunoreactivity (LI) and gastrin in the serum were determined by radioimmunoassay. Results The serum Pancreastatin-LI concentration was lowered by about 80% by fundectomy and gastrectomy; both of these procedures eliminated the ECL cell population. Adrenalectomy had no effect on the serum Pancreastatin-LI concentration. Gastrin infusion, which activates the ECL cells, promptly increased serum Pancreastatin-LI concentration. Refeeding after fasting and administration of omeprazole or ranitidine increased the serum Pancreastatin-LI concentrations; these responses were prevented by antrectomy. Conclusions The concentration of circulating Pancreastatin-LI reflects the activity of the ECL cells and the size of the ECL cell population in the rat stomach.
