Proglucagon-Derived Peptides in the Neuroendocrine System

Brubaker, P. L.; Stobie, K.; Roberge, Jean‐Baptiste; Lui, E Y; Drucker, Daniel J.

doi:10.1007/978-1-4684-5931-9_12

Cited by 2 publications

(4 citation statements)

References 33 publications

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“…Synthesis and secretion of the Pgdp's is also stimu lated by activation of protein kinase A in the pancreas and intestine [3,13,20,22]. However, protein kinase A path way stimulation stimulates the Pgdp's by only 2-fold in intestinal [13,22] and pancreatic islet [22] cultures whereas 5-to 10-fold increases were observed in the fetal rat hypothalamic cultures in the present study ( fig.…”

Section: Discussioncontrasting

confidence: 49%

“…However, protein kinase A path way stimulation stimulates the Pgdp's by only 2-fold in intestinal [13,22] and pancreatic islet [22] cultures whereas 5-to 10-fold increases were observed in the fetal rat hypothalamic cultures in the present study ( fig. 4).…”

Section: Discussionmentioning

confidence: 43%

“…The results of the 24-hour protein kinase A and pro tein kinase C experiments are summarized in figure 4 for the hypothalamic Pgdp's, and are contrasted to the data obtained from similar experiments carried out on intesti nal [3,13] and pancreatic [20][21][22] Pgdp-producing cells. The effect of protein kinase A stimulation on GLI secre tion in the hypothalamus was significantly greater than in the pancreas or intestine (p < 0.01 and 0.001, respec tively).…”

Section: Resultsmentioning

confidence: 71%

“…The lack of effect of PMA on Pgdp biosynthesis is not surprising in light of the fact that the proglucagon gene does not contain the heptameric cis regulatory sequence (TRE) that is necessary for protein kinase C to affect gene transcription via the AP-L transactivating factor [22,30,31 ]. These results are consistent with our findings of a lack of effect of PMA on Pgdp synthesis in the intestine [3,13] and different from the slight (less than 2-fold) stimulatory effect of PMA on Pgdp synthesis in the pancreas [p < 0.05, unpubl.…”

Section: Discussionmentioning

confidence: 99%

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Control of Proglucagon-Derived Peptide Synthesis and Secretion in Fetal Rat Hypothalamus

Stobie-Hayes

Brubaker²

1992

Neuroendocrinology

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The hypothalamus has the highest concentration of proglucagon-derived peptides (Pgdp’s) in the brain, however, the control of the synthesis and secretion of these peptides is not understood. The goal of our studies was to examine in detail the regulation of synthesis and secretion of Pgdp’s in the hypothalamus. Hypothalamic cultures were prepared from fetal rats on day 19–21 of gestation and Pgdp’s in media and cells were determined by radioimmunoassay after treatment with test agents. Dibutyryl cyclic AMP or forskolin, activators of protein kinase A, markedly stimulated both Pgdp synthesis (by 5-fold) and secretion (by 10-fold) after 24 h of treatment (p < 0.05). The effects of protein kinase A stimulation on Pgdp’s in the hypothalamus were greater than seen in our previous studies with the Pgdp-producing pancreatic A and intestinal L cells. Therefore there are tissue-specific differences with regard to the magnitude of the response of Pgdp’s to protein kinase A stimulation. Consistent with an involvement of protein kinase A in hypothalamic Pgdp synthesis and secretion, somatostatin-14, an inhibitor of protein kinase A, was found to inhibit Pgdp synthesis and secretion in a dose-dependent fashion (p < 0.05). Phorbol myristate acetate (PMA), a stimulator of protein kinase C, did not significantly affect the synthesis or secretion of Pgdp’s at 6 h, but significantly stimulated Pgdp secretion after 24 h (p < 0.05). The inactive phorbol ester, phorbol triacetate was without effect on Pgdp synthesis or secretion after 24 h of incubation (p > 0.05). Protein kinase C stimulation was previously shown to increase Pgdp secretion, but not synthesis in the pancreas and intestine, an effect similar to that seen in the hypothalamus. However, the effects of PMA on Pgdp secretion were seen at 2 and 24 h in the intestine but only at 24 h in the hypothalamus. Gastrin-releasing peptide, a hypothalamic peptide that stimulates protein kinase C, had no effect on Pgdp production in the hypothalamus (p > 0.05). In conclusion, our studies have shown both similarities and differences in the regulation of Pgdp synthesis and secretion by protein kinase A and C in the hypothalamus, as compared to the pancreatic A and intestinal L cell.

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Section: Discussioncontrasting

confidence: 49%

Section: Discussionmentioning

confidence: 43%

Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Control of Proglucagon-Derived Peptide Synthesis and Secretion in Fetal Rat Hypothalamus

Stobie-Hayes

Brubaker²

1992

Neuroendocrinology

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Processing of Mouse Proglucagon by Recombinant Prohormone Convertase 1 and Immunopurified Prohormone Convertase 2 in Vitro

Rothenberg

Eilertson

Klein

et al. 1995

Journal of Biological Chemistry

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The mouse tumor cell line alpha TC1-6 was used as a model system to examine the post-translational processing of proglucagon. Determination of the mouse preproglucagon cDNA sequence and comparison with the published sequences of rat and human preproglucagons revealed nucleic acid homologies of 89.1 and 84%, respectively, and amino acid homologies of 94 and 89.4%, respectively. Immunohistochemical analyses with antibodies directed against PC2 and glucagon colocalized both the enzyme and substrate within the same secretory granules. PC1 was also immunolocalized in secretory granules. Cells were metabolically labeled with [3H]tryptophan, and extracts were analyzed by reverse-phase high pressure liquid chromatography. Radioactive peptides with retention times identical to those of synthetic peptide standards were recovered and subjected to peptide mapping to verify their identities. To determine the potential role of PC1 and PC2 in proglucagon processing, 3H-labeled proglucagon was incubated in vitro with recombinant PC1 and/or immunopurified PC2. Both enzymes cleaved proglucagon to yield the major proglucagon fragment, glicentin, and oxyntomodulin, whereas only PC1 released glucagon-like peptide-I from the major proglucagon fragment. Neither PC1 nor PC2 processed glucagon from proglucagon in vitro. These results suggest a potential role for PC1 and/or PC2 in cleaving several of the normal products, excluding glucagon, from the mouse proglucagon precursor.

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Proglucagon-Derived Peptides in the Neuroendocrine System

Cited by 2 publications

References 33 publications

Control of Proglucagon-Derived Peptide Synthesis and Secretion in Fetal Rat Hypothalamus

Control of Proglucagon-Derived Peptide Synthesis and Secretion in Fetal Rat Hypothalamus

Processing of Mouse Proglucagon by Recombinant Prohormone Convertase 1 and Immunopurified Prohormone Convertase 2 in Vitro

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