The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
Reiner Fischercolbrie - One of the best experts on this subject based on the ideXlab platform.
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secretogranin ii novel insights into expression and function of the precursor of the neuropeptide secretoneurin
2017Co-Authors: Reiner Fischercolbrie, Markus Theurl, Rudolf KirchmairAbstract:SgII is an acidic secretory which belongs to the family of Chromogranins. It is present in the large-dense cored vesicles of the regulated secretory pathway of many neurons and endocrine cells and it is well conserved during evolution. Like Chromogranin A, SgII can induce granulogenesis in endocrine cells but also in cells typically lacking secretory vesicles like fibroblasts. In the secretory vesicles SgII is processed to smaller peptides, e.g. secretoeneurin, EM66 and manserin. For secretoneurin several biological effects like induction of neurotransmitter release, chemotactic activity towards immune-, endothelial- and muscle cells, and potent angiogenic and vasculogenic properties have been established. Thus, SN displays potent hormonal and paracrine effects, which help to orchestrate development, maintenance, physiologic activity and repair of the surrounding tissue. In addition, SgII has been established as valuable biomarker for endocrine tumours and cardiovascular diseases.
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the extended granin family structure function and biomedical implications
Endocrine Reviews, 2011Co-Authors: Alessandro Bartolomucci, Reiner Fischercolbrie, Roberta Possenti, Sushil K Mahata, Peng Y Loh, Sushil K Mahata, Stephen R J SaltonAbstract:The Chromogranins (Chromogranin A and Chromogranin B), secretogranins (secretogranin II and secretogranin III), and additional related proteins (7B2, NESP55, proSAAS, and VGF) that together comprise the granin family subserve essential roles in the regulated secretory pathway that is responsible for controlled delivery of peptides, hormones, neurotransmitters, and growth factors. Here we review the structure and function of granins and granin-derived peptides and expansive new genetic evidence, including recent single-nucleotide polymorphism mapping, genomic sequence comparisons, and analysis of transgenic and knockout mice, which together support an important and evolutionarily conserved role for these proteins in large dense-core vesicle biogenesis and regulated secretion. Recent data further indicate that their processed peptides function prominently in metabolic and glucose homeostasis, emotional behavior, pain pathways, and blood pressure modulation, suggesting future utility of granins and granin-derived peptides as novel disease biomarkers.
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secretoneurin in carcinoids of the appendix immunohistochemical comparison with Chromogranins a b and secretogranin ii
Anticancer Research, 1998Co-Authors: Rupert Prommegger, Reiner Fischercolbrie, Peter Obrist, Christian Ensinger, H G Schwelberger, C Wolf, Gregor Mikuz, E BodnerAbstract:Background: The aim of the present study was to investigate immunohistochemically the distribution of secretoneurin, a novel 33 amino acid peptide, in comparison to Chromogranin A, Chromogranin B, and secretogranin II in carcinoids of the appendix Materials and Methods: Paraffin-embedded tissues from 47 carcinoids were incubated with antibodies specific for Chromogranin A, Chromogranin B, the secretogranin II derived peptide LF- 19, and secretoneurin. Results: 44 tumors (94%) were positive for secretoneurin, whereas only 39 tumors (83%) were immunoreactive for Chromogranin A. There was no significant correlation between neuropeptide expression and type of carcinoid, tumor size, vascular infiltration, serosal involvement or mesoappendiceal infiltration. Conclusions: Our investigations revealed that secretoneurin is detected more frequently than Chromogranin A in carcinoids of the appendix. This supports the theory that tumor cells of appendiceal carcinoids are of a different origin than other midgut carcinoids. No special tumor entity with a characteristic secretoneurin-Chromogranin pattern could be identified.
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immunohistochemical distribution of Chromogranins a and b and secretogranin ii in neuroendocrine tumours of the gastrointestinal tract
Virchows Archiv, 1995Co-Authors: A G Fahrenkamp, Reiner Fischercolbrie, C Wibbeke, G Winde, Dietmar Ofner, W Bocker, W Bocker, K W SchmidAbstract:The aim of the present study was to investigate immunohistochemically the distribution of Chromogranin A, Chromogranin B, and secretogranin II in a series of 152 neuroendocrine tumours of the gastrointestinal tract. Tumour tissues from 25 argyrophil gastric carcinoids, 18 gastrin and 5 somatostatin-producing tumours, 4 ‘gangliocytic paragangliomas’, 49 classical argentaffin and 2 L cell appendiceal carcinoids, 27 classical ileal carcinoids, 17 rectal carcinoids, and 5 poorly differentiated neuroendocrine tumours of the stomach and rectum were immunostained with antibodies against Chromogranin A, Chromogranin B, and secretogranin II. Chromogranin A was the major granin expressed in gastric carcinoids and in serotonin-producing carcinoids of the appendix and the ileum. In contrast, strong Chromogranin B and secretogranin II immunoreactivity was found in rectal carcinoids, in which Chromogranin A was rarely expressed. Since Chromogranin A is a widely used marker for neuroendocrine differentiation, it is of diagnostic importance that some gastrin-producing tumours, ‘gangliocytic paragangliomas’, poorly differentiated neuroendocrine carcinomas, and appendiceal L cell carcinoids completely lacked Chromogranin A positivity. It is concluded that the various neuroendocrine tumours of the gastrointestinal tract show distinctly different patterns of granin expression, probably reflecting their histogenetical origin.
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molecular characterization of immunoreactivities of peptides derived from Chromogranin a ge 25 and from secretogranin ii secretoneurin in human and bovine cerebrospinal fluid
Neuroscience, 1994Co-Authors: Rudolf Kirchmair, Ruth Hogueangeletti, Reiner Fischercolbrie, A Benzer, Josef Troger, C H Miller, J Marksteiner, Alois Saria, R W Gasser, H WinklerAbstract:Abstract Chromogranin A and secretogranin II are members of the so-called Chromogranins, the acidic proteins stored in neuroendocrine large dense-core vesicles. We characterized Chromogranin A and secretogranin II immunoreactivities in cerebrospinal fluid by radioimmunoassays using synthetic peptides derived from these components (GE-25 for Chromogranin A and secretoneurin for secretogranin II). In lumbar cerebrospinal fluid, high levels (more than 1000 fmol/ml) of these two components were found, whereas in ventricular cerebrospinal fluid the secretoneurin levels were relatively low. The cerebrospinal fluid/serum ratio for secretoneurin was close to 170. High-performance liquid chromatography revealed that in both cerebrospinal fluid and extracts from human brain secretoneurin was the predominant immunoreactive component. In cerebrospinal fluid Chromogranin A immunoreactivity was present as intermediate-sized peptides with little intact Chromogranin A and free GE-25 peptide. In human brain samples smaller peptides including GE-25 were more predominant. Analogous findings for secretoneurin and Chromogranin A were obtained for bovine brain samples. We can conclude that Chromogranins are present in cerebrospinal fluid in concentrations much higher than those of classical neuropeptides also stored in large dense-core vesicles. Therefore, their degree of proteolytic processing can be analysed with small samples of cerebrospinal fluid. A possible disturbance of proteolytic processing in large dense-core vesicles in various pathological conditions can now be discovered.
Mariehelene Metzboutigue - One of the best experts on this subject based on the ideXlab platform.
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characterization and location of post translational modifications on Chromogranin b from bovine adrenal medullary chromaffin granules
Proteomics, 2004Co-Authors: Claire Gasnier, Dominique Aunis, Jeanmarc Strub, Karine Lugardon, Olivier Ruh, Mariehelene MetzboutigueAbstract:Bovine chromoganin B (CGB)/secretogranin I, an acidic protein with a sequence of 626 residues and an isoelectric point of 5.2 is a major member of the Chromogranin/secretogranin (CG/Sg) family. The difference between the theoretical molecular mass (76 kDa) and the value estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis results from post-translational modifications (glycosylation, phosphorylation and sulfation) and from the abundance of acidic residues (D 4.6%, and E 16.5%). Although the sequence of CGB is known, the structural analyses of the post-translational modifications have so far not been carried out. In the present study, using a combination of proteomic techniques including two-dimensional gel electrophoresis, Western blot, high-performance liquid chromatography purification, enzymatic digestion, sequencing, carbohydrate analysis, matrix-assisted laser desorption/ionization-time of flight and liquid chromatography mass spectrometry analysis, we have located 18 post-translational modifications on bovine CGB, isolated from adrenal medulla chromaffin granules. Furthermore, we have identified at the molecular level the presence of a mutation M/V on position 577 of natural CGB. All together these data reflect the complex structure of this protein marker of the neuroendocrine system.
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antimicrobial Chromogranins and proenkephalin a derived peptides
Annals of the New York Academy of Sciences, 2003Co-Authors: Dominique Aunis, Mariehelene Metzboutigue, Jeanmarc Strub, Yannick Goumon, Karine LugardonAbstract:: The secretory granules from adrenal medullary chromaffin cells contain a complex mixture of low-molecular mass constituents such as catecholamines, ascorbate, nucleotides, calcium, peptides, and several high-molecular mass water-soluble proteins including Chromogranins and proenkephalin-A. These proteins are sequestered into secretory granules in which processing yields a large variety of peptides. These fragments are released into the extracellular space upon cell stimulation and are recovered in blood, lymph, cerebrospinal fluid, and synovial fluid. Some of them have biological activity on cells in an autocrine, paracrine, or endocrine fashion. In addition, we have shown that peptides with antimicrobial activity are present with the secretory chromaffin granules and demonstrated that they are released from stimulated chromaffin cells. We have shown that posttranslational modifications modulate the antimicrobial activities. For some peptides, using confocal laser microscopy, we have examined the interaction of the rhodaminated peptides with biological membranes. In addition, we have shown that chromofungin, the antifungal peptide corresponding to Chromogranin A47–66, can bind calmodulin in the presence of calcium and induce inhibition of calcineurin, a calmodulin-dependent enzyme. Because these antibacterial peptides are colocalized with catecholamines, they may be activated during stress, playing a role as a first protective barrier against bacterial infection, and thus act as factors of the innate immunity shortly after infection and before the induction and mobilization of an adaptative immune system.
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antibacterial activity of glycosylated and phosphorylated Chromogranin a derived peptide 173 194 from bovine adrenal medullary chromaffin granules
Journal of Biological Chemistry, 1996Co-Authors: Jeanmarc Strub, Dominique Aunis, Yannick Goumon, Karine Lugardon, Calliope Capon, Michel Lopez, M Moniatte, Alain Van Dorsselaer, Mariehelene MetzboutigueAbstract:Recently, we have isolated from bovine chromaffin granules and identified two natural peptides possessing antibacterial activity: secretolytin (Chromogranin B 614-626) and enkelytin (proenkephalin-A 209-237). Here, we characterize a large natural fragment, corresponding to Chromogranin A 79-431, that inhibits growth of both Gram-positive and Gram-negative bacteria. The aim of the present work was to determine the shortest active peptide located in the 79-431 Chromogranin A region. Three peptides, which shared the same 173-194 Chromogranin A sequence (YPGPQAKEDSEGPSQGPASREK) but differed in post-translational modifications, including O-glycosylation and tyrosine phosphorylation, were isolated. A detailed study using microsequencing and mass spectrometry allowed us to correlate their antibacterial activity with these post-translational modifications. The Chromogranin A precursor fragment (79-431) and the active glycosylated and phosphorylated peptides were, respectively, named prochromacin and chromacin (P, G, and PG for phosphorylated, glycosylated, and phosphorylated-glycosylated form).
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the c terminal bisphosphorylated proenkephalin a 209 237 peptide from adrenal medullary chromaffin granules possesses antibacterial activity
FEBS Journal, 1996Co-Authors: Yannick Goumon, Pierre Hubert, Dominique Aunis, Jeanmarc Strub, M Moniatte, Alain Van Dorsselaer, Gerard Nullans, Livia Poteur, Mariehelene MetzboutigueAbstract:The chromaffin granules have been shown to be an excellent model to study the processing of proenkephalin-A and Chromogranins. Recently, we reported a study dealing with the processing of Chromogranin B/secretogranin I and the occurrence of the C-terminal Chromogranin B-derived peptide 614–626 which was shown to have antibacterial activity [Strub, J. M., Garcia-Sablone, P., Looning, K., Taupenol, L., Hubert, P., Van Dorsselaer, A., Aunis, D. & Metz-Boutigue, M. H. (1995) Eur. J. Biochem. 229, 356–368], We also observed that this new antibacterial activity present in chromaffin granules was associated with other endogenous protein-derived fragments yet to be characterized. The present study reports the isolation and characterization of a peptide which possesses antibacterial activity and which corresponds to the C-terminal 209–237 sequence of proenkephalin-A. A detailed study using microsequencing and matrix-assisted-laser-desorption time-of-flight mass spectrometry (MALD-TOF MS) allowed us to correlate the antibacterial activity of this peptide named enkelytin (FAEPLPSEEEGESYSKEVPEMEKRYGGFM) with post-translational modifications. Endogenous bisphosphorylated proenkephalin-A-(209–237) was active on Micrococcus luteus and Bacillus megaterium killing bacteria in the 0.2–0.4 μM range but was inactive in similar conditions towards Escherichia coli. Enkelytin shares sequence and structural similarities with the antibacterial C-terminal domain of diazepam-binding inhibitor. According to this similarity, a prediction of secondary structure is proposed for enkelytin and discussed in relation to its biological activity.
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processing of Chromogranin b in bovine adrenal medulla identification of secretolytin the endogenous c terminal fragment of residues 614 626 with antibacterial activity
FEBS Journal, 1995Co-Authors: J M Strub, Pascale Garciasablone, Kjersti Lonning, Laurent Taupenot, Pierre Hubert, Alain Van Dorsselaer, Dominique Aunis, Mariehelene MetzboutigueAbstract:Chromogranins constitute a family of acidic soluble proteins widely distributed in endocrine cells and neurons. Chromogranin A, the major soluble component in bovine adrenal medullary secretory granules in chromaffin cells, has been shown to be actively processed to peptide fragments [Metz-Boutigue, M. H., Garcia-Sablone, P., Hogue-Angeletti, R. & Aunis, D. (1993) Eur. J. Biochem. 217, 247-257]. In the present paper, the structural features of the proteolytic degradation mechanism of Chromogranin B/secretogranin I have been characterized with regard to the possible function of this protein as a precursor of biologically active peptides. Chromogranin-B-derived fragments present in bovine chromaffin granules were identified by microsequencing after separation by two-dimensional gel electrophoresis or high-performance liquid chromatography. A similar approach was performed to characterize Chromogranin-B-derived fragments released into the extracellular space from depolarized bovine cultured chromaffin cells. In Chromogranin B, 18 cleavage sites were identified along the protein chain and Chromogranin B/secretogranin I fragments were generated by proteolytic attack at both the N-terminus and C-terminus. A major fragment corresponding to residues 614-626 of the C-terminal sequence, was identified in the extracellular space; this peptide was found to share sequence and structural similarities with the lytic domain of cecropins and, as expected from this similarity, to display potent antibacterial properties. Endogenous and synthetic peptides were active on Micrococus luteus, killing bacteria in the micromolar concentration range. The synthetic peptide slows the growth of Bacillus megaterium and was inactive towards Escherichia coli. In addition, the synthetic peptide was unable to induce hemolytic activity. This antibacterial function might be of biological significance in the neuroendocrine system of living organisms. We propose to name this peptide secretolytin.
K W Schmid - One of the best experts on this subject based on the ideXlab platform.
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immunohistochemical distribution of Chromogranins a and b and secretogranin ii in neuroendocrine tumours of the gastrointestinal tract
Virchows Archiv, 1995Co-Authors: A G Fahrenkamp, Reiner Fischercolbrie, C Wibbeke, G Winde, Dietmar Ofner, W Bocker, W Bocker, K W SchmidAbstract:The aim of the present study was to investigate immunohistochemically the distribution of Chromogranin A, Chromogranin B, and secretogranin II in a series of 152 neuroendocrine tumours of the gastrointestinal tract. Tumour tissues from 25 argyrophil gastric carcinoids, 18 gastrin and 5 somatostatin-producing tumours, 4 ‘gangliocytic paragangliomas’, 49 classical argentaffin and 2 L cell appendiceal carcinoids, 27 classical ileal carcinoids, 17 rectal carcinoids, and 5 poorly differentiated neuroendocrine tumours of the stomach and rectum were immunostained with antibodies against Chromogranin A, Chromogranin B, and secretogranin II. Chromogranin A was the major granin expressed in gastric carcinoids and in serotonin-producing carcinoids of the appendix and the ileum. In contrast, strong Chromogranin B and secretogranin II immunoreactivity was found in rectal carcinoids, in which Chromogranin A was rarely expressed. Since Chromogranin A is a widely used marker for neuroendocrine differentiation, it is of diagnostic importance that some gastrin-producing tumours, ‘gangliocytic paragangliomas’, poorly differentiated neuroendocrine carcinomas, and appendiceal L cell carcinoids completely lacked Chromogranin A positivity. It is concluded that the various neuroendocrine tumours of the gastrointestinal tract show distinctly different patterns of granin expression, probably reflecting their histogenetical origin.
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Expression of Chromogranin A and B and secretoneurin immunoreactivity in neoplastic and nonneoplastic pancreatic alpha cells
Virchows Archiv, 1994Co-Authors: K W Schmid, Reiner Fischer-colbrie, M. Brink, G. Freytag, W. Böcker, R. Kirchmair, P. Heitz, W Bocker, G. KlöppelAbstract:In the endocrine pancreas, Chromogranins A and B as well as secretoneurin (a biologically active peptide processed endoproteolytically from secretogranin II) are most intensely expressed in alpha (glucagon) cells. We examined whether the functional status of neoplastic and nonneoplastic human alpha cells is reflected in the expression patterns of Chromogranins/secretogranins. Neoplastic alpha cells were analysed immunocytochemically in six functioning glucagonomas and 37 nonfunctioning neuroendocrine tumours (29 with alpha cells) for their immunoreactivity to Chromogranin A and B, as well as secretoneurin. There was no difference in the staining intensity for either peptide between glucagonomas and nonfunctioning, alpha cell containing tumours. Nonneoplastic alpha cells from patients with a functioning glucagonoma showed a decreased glucagon immunoreactivity, whereas the expression of Chromogranin A (but not Chromogranin B and secretoneurin) was as intense as in alpha cells not associated with glucagonoma syndrome. These results suggest that the expression of Chromogranins/secretogranins in neoplastic alpha cells of the pancreas may be independently regulated from the cells' functional status. In nonneoplastic alpha cells there seems to be an association between glucagon production and Chromogranin B and secretoneurin expression.
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immunohistochemical localization of Chromogranins a and b and secretogranin ii in normal hyperplastic and neoplastic prostate
Histopathology, 1994Co-Authors: K W Schmid, Reiner Fischercolbrie, Rudolf Kirchmair, W Bocker, B Helpap, M Totsch, Barbara DockhorndworniczakAbstract:Routinely processed normal, hyperplastic and neoplastic prostatic tissue was immunohistochemically investigated with antibodies against Chromogranin A and B and secretogranin II. In normal and hyperplastic prostates all three peptides were immunolocalized in scattered neuroendocrine cells situated within the glandular epithelium. In 17 prostatic carcinomas with pronounced neuroendocrine differentiation and in a case of prostatic carcinoid, Chromogranin B was the major component whereas Chromogranin A and secretogranin II were virtually absent in poorly differentiated (grade III) tumours. Neuroendocrine differentiation in prostatic cancer is most likely to be associated with a poor clinical outcome; thus, Chromogranin B appears to be a useful marker in the histopathological diagnosis of these neoplasms.
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immunohistochemical comparison of Chromogranins a and b and secretogranin ii with calcitonin and calcitonin gene related peptide expression in normal hyperplastic and neoplastic c cells of the human thyroid
Histopathology, 1992Co-Authors: K W Schmid, Reiner Fischercolbrie, Rudolf Kirchmair, D Ladurner, W BockerAbstract:Normal and hyperplastic thyroid C-cells and 14 cases of medullary thyroid carcinoma were investigated immunohistochemically with antibodies against Chromogranins A and B, secretogranin II, calcitonin and calcitonin gene-related peptide (CGRP). Normal and hyperplastic C-cells showed strong calcitonin and Chromogranin A immunoreactivity whereas CGRP, Chromogranin B and secretogranin II expression was less intense. Strong calcitonin and Chromogranin A immunoreactivity was also found in the majority of tumour cells in medullary thyroid carcinoma. The CGRP, Chromogranin B and secretogranin II staining observed was present in variable patterns. In some cases CGRP, Chromogranin B and secretogranin II could only be demonstrated in isolated tumour cells with elongated processes suggestive of neuronal differentiation of these cells. The biological function(s) of the Chromogranins/secretogranins remain(s) still unclear. There is evidence that these proteins are pro-peptides which give rise to functionally active compounds. Studies on normal C-cells and medullary thyroid carcinoma may elucidate the role of Chromogranins/secretogranins in endocrine and neuronal cells.
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sex related differences in Chromogranin a Chromogranin b and secretogranin ii gene expression in rat pituitary
Journal of Neuroendocrinology, 1992Co-Authors: Reiner Fischercolbrie, K W Schmid, Andrea Laslop, Sushil K Mahata, Manjula Mahata, Sushil K Mahata, Manjula Mahata, J. W. BauerAbstract:Chromogranin A, an acidic secretory protein, is widely distributed throughout diverse endocrine cells and the central and peripheral nervous systems. Chromogranin A is co-stored and co-secreted from secretory vesicles together with the endogenous hormones or neurotransmitters. Recently, two peptides derived from the Chromogranin A precursor have been shown to inhibit secretion from endocrine cells. In the present study, we investigated the regulation of the biosynthesis of Chromogranin A by estrogen in various tissues. In the pituitary, steady-state levels of Chromogranin A mRNA were markedly reduced by 64% in estrogen-treated male rats. At the protein level, a comparable decrease was found. Chromogranin B and secretogranin II, two other secretory proteins co-stored with Chromogranin A, were slightly increased by estrogen. In pituitaries of female rats Chromogranin A mRNA and protein levels were significantly lower than in males. For Chromogranin B on the other hand, a 2-fold increase of mRNA levels was found. Our observations demonstrate that physiologic concentrations of estrogen strongly affect Chromogranin A levels in the pituitary resulting in a sex-related difference in Chromogranin A gene expression. Based on these and previous results demonstrating increased biosynthesis of Chromogranin A by glucocorticoids and calciferol, we suggest that a typical and characteristic feature of the Chromogranin A gene is its regulation by at least three different classes of steroid hormones.
Daniel T Oconnor - One of the best experts on this subject based on the ideXlab platform.
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the crucial role of Chromogranins in storage and exocytosis revealed using chromaffin cells from Chromogranin a null mouse
The Journal of Neuroscience, 2008Co-Authors: Monica S Montesinos, David J Machado, Marcial Camacho, Jesica Diaz, Yezer G Morales, Diego Alvarez De La Rosa, Emilia Carmona, Agustin Castaneyra, Humberto O Viveros, Daniel T OconnorAbstract:Chromogranins (Cgs) are the major soluble proteins of dense-core secretory vesicles. Chromaffin cells from Chga null mice [Chromogranin A knock-out (CgA-KO)] exhibited approximately 30% reduction in the content and in the release of catecholamines compared with wild type. This was because of a lower secretion per single exocytotic event, rather than to a lower frequency of exocytotic events. Cell incubation with L-DOPA produced an increase in the vesicular amine content of wild-type, but not CgA-KO vesicles. In contrast, intracellular electrochemistry showed that L-DOPA produced a significantly larger increase in cytosolic amines in CgA-KO cells than in the wild type. These data indicate that the mechanisms for vesicular accumulation in CgA-KO cells were fully saturated. Patch-amperometry recordings showed a delayed initiation of the amperometric signal after vesicle fusion, whereas no changes were observed in vesicle size or fusion pore kinetics despite the smaller amine content. We conclude that intravesicular proteins are highly efficient systems directly implicated in transmitter accumulation and in the control of neurosecretion.
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the Chromogranin secretogranin family
The New England Journal of Medicine, 2003Co-Authors: Laurent Taupenot, Kimberly L Harper, Daniel T OconnorAbstract:The members of the Chromogranin–secretogranin family of peptide hormones, biogenic amines, and neurotransmitters are enclosed within vesicles in the neuroendocrine system and a variety of neurons. These granins, the chief of which is Chromogranin A, participate in sympathoadrenal activity and serve as markers of neuroendocrine tumors, especially pheochromocytoma.
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malignant pheochromocytoma chromaffin granule transmitters and response to treatment
Hypertension, 2000Co-Authors: Harry R Keiser, Daniel T OconnorAbstract:Abstract —Chromaffin granule transmitters such as Chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of Chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (n=27), both benign (n=13) and malignant (n=14). Patients with benign pheochromocytoma were studied before and after surgical excision (n=6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in n=9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (n=5) versus nonresponders (n=4). Plasma Chromogranin A rose progressively ( P P P =0.0182). In bivariate analyses, Chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all P P =0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate ( P =0.0003) and multivariate ( P =0.011) analyses. After excision of benign pheochromocytoma, Chromogranin A ( P =0.028), norepinephrine ( P =0.047), and epinephrine ( P =0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (n=9), plasma Chromogranin A ( P =0.047) and norepinephrine ( P =0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in Chromogranin A ( P =0.03) and norepinephrine ( P =0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma Chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma Chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated Chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, Chromogranin A can be used to gauge tumor response and relapse.
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novel autocrine feedback control of catecholamine release a discrete Chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist
Journal of Clinical Investigation, 1997Co-Authors: Sushil K Mahata, Daniel T Oconnor, Bruce M Gill, L Taupenot, Seung Hyun Yoo, Manjula Mahata, Sushil K Mahata, Manjula Mahata, Seung Hyun Yoo, R J ParmerAbstract:Catecholamine secretory vesicle core proteins (Chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated Chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed Chromogranin fragments, and was liberated from purified Chromogranin A. Of 15 synthetic peptides spanning approximately 80% of Chromogranin A, one (bovine Chromogranin A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 approximately 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of Chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of Chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this Chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within Chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.
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stimulus coupling to transcription versus secretion in pheochromocytoma cells convergent and divergent signal transduction pathways and the crucial roles for route of cytosolic calcium entry and protein kinase c
Journal of Clinical Investigation, 1997Co-Authors: Kechun Tang, Bruce M Gill, Robert J Parmer, Sushil K Mahata, Manjula Mahata, Daniel T OconnorAbstract:How do chromaffin cell secretory stimuli program resynthesis of secreted peptides and amines? We previously showed that the physiologic nicotinic cholinergic signal for secretion also activates the biosynthesis of Chromogranin A, the major protein released with catecholamines. Here, we examine signal transduction pathways whereby secretory stimuli influence exocytotic secretion versus Chromogranin A transcription. Both secretion and transcription depended on initial nicotinic-triggered sodium entry into the cytosol, followed by calcium entry through -type voltage-gated channels. When calcium entered through -type channels, activation of secretion paralleled activation of transcription (r = 0.897, P = 0.002). Calcium entry from intracellular stores or through calcium ionophore channels activated secretion, though not transcription. Nicotinic-stimulated transcription depended upon protein kinase C activation; nicotine caused translocation of protein kinase C to the cell membrane fraction, and inhibition of protein kinase C blocked activation of transcription, while activation of protein kinase C mimicked nicotine effects. Transcriptional responses to both nicotine and protein kinase C mapped principally onto the Chromogranin A promoter's cAMP response element (TGACGTAA; CRE box). KCREB, a dominant negative mutant of the CRE-binding protein CREB, blunted activation of Chromogranin A transcription by nicotine, phorbol ester, or membrane depolarization. We conclude that activation of Chromogranin A transcription by secretory stimulation in chromaffin cells is highly dependent upon precise route of calcium entry into the cytosol; transcription occurred after entry of calcium through -type channels on the cell surface, and was mediated by protein kinase C activation. The trans-acting factor CREB ultimately relays the secretory signal to the Chromogranin A promoter's CRE box in cis.
Rudolf Kirchmair - One of the best experts on this subject based on the ideXlab platform.
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secretogranin ii novel insights into expression and function of the precursor of the neuropeptide secretoneurin
2017Co-Authors: Reiner Fischercolbrie, Markus Theurl, Rudolf KirchmairAbstract:SgII is an acidic secretory which belongs to the family of Chromogranins. It is present in the large-dense cored vesicles of the regulated secretory pathway of many neurons and endocrine cells and it is well conserved during evolution. Like Chromogranin A, SgII can induce granulogenesis in endocrine cells but also in cells typically lacking secretory vesicles like fibroblasts. In the secretory vesicles SgII is processed to smaller peptides, e.g. secretoeneurin, EM66 and manserin. For secretoneurin several biological effects like induction of neurotransmitter release, chemotactic activity towards immune-, endothelial- and muscle cells, and potent angiogenic and vasculogenic properties have been established. Thus, SN displays potent hormonal and paracrine effects, which help to orchestrate development, maintenance, physiologic activity and repair of the surrounding tissue. In addition, SgII has been established as valuable biomarker for endocrine tumours and cardiovascular diseases.
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levels and proteolytic processing of Chromogranin a and b and secretogranin ii in cerebrospinal fluid in neurological diseases
Journal of Neural Transmission, 1998Co-Authors: U Eder, Rudolf Kirchmair, A Benzer, B Leitner, P Pohl, K A Jobst, A D Smith, J Mally, P Riederer, H ReichmannAbstract:Human cerebrospinal fluid (CSF) contains Chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of Chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay.
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molecular characterization of immunoreactivities of peptides derived from Chromogranin a ge 25 and from secretogranin ii secretoneurin in human and bovine cerebrospinal fluid
Neuroscience, 1994Co-Authors: Rudolf Kirchmair, Ruth Hogueangeletti, Reiner Fischercolbrie, A Benzer, Josef Troger, C H Miller, J Marksteiner, Alois Saria, R W Gasser, H WinklerAbstract:Abstract Chromogranin A and secretogranin II are members of the so-called Chromogranins, the acidic proteins stored in neuroendocrine large dense-core vesicles. We characterized Chromogranin A and secretogranin II immunoreactivities in cerebrospinal fluid by radioimmunoassays using synthetic peptides derived from these components (GE-25 for Chromogranin A and secretoneurin for secretogranin II). In lumbar cerebrospinal fluid, high levels (more than 1000 fmol/ml) of these two components were found, whereas in ventricular cerebrospinal fluid the secretoneurin levels were relatively low. The cerebrospinal fluid/serum ratio for secretoneurin was close to 170. High-performance liquid chromatography revealed that in both cerebrospinal fluid and extracts from human brain secretoneurin was the predominant immunoreactive component. In cerebrospinal fluid Chromogranin A immunoreactivity was present as intermediate-sized peptides with little intact Chromogranin A and free GE-25 peptide. In human brain samples smaller peptides including GE-25 were more predominant. Analogous findings for secretoneurin and Chromogranin A were obtained for bovine brain samples. We can conclude that Chromogranins are present in cerebrospinal fluid in concentrations much higher than those of classical neuropeptides also stored in large dense-core vesicles. Therefore, their degree of proteolytic processing can be analysed with small samples of cerebrospinal fluid. A possible disturbance of proteolytic processing in large dense-core vesicles in various pathological conditions can now be discovered.
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immunohistochemical localization of Chromogranins a and b and secretogranin ii in normal hyperplastic and neoplastic prostate
Histopathology, 1994Co-Authors: K W Schmid, Reiner Fischercolbrie, Rudolf Kirchmair, W Bocker, B Helpap, M Totsch, Barbara DockhorndworniczakAbstract:Routinely processed normal, hyperplastic and neoplastic prostatic tissue was immunohistochemically investigated with antibodies against Chromogranin A and B and secretogranin II. In normal and hyperplastic prostates all three peptides were immunolocalized in scattered neuroendocrine cells situated within the glandular epithelium. In 17 prostatic carcinomas with pronounced neuroendocrine differentiation and in a case of prostatic carcinoid, Chromogranin B was the major component whereas Chromogranin A and secretogranin II were virtually absent in poorly differentiated (grade III) tumours. Neuroendocrine differentiation in prostatic cancer is most likely to be associated with a poor clinical outcome; thus, Chromogranin B appears to be a useful marker in the histopathological diagnosis of these neoplasms.
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immunohistochemical comparison of Chromogranins a and b and secretogranin ii with calcitonin and calcitonin gene related peptide expression in normal hyperplastic and neoplastic c cells of the human thyroid
Histopathology, 1992Co-Authors: K W Schmid, Reiner Fischercolbrie, Rudolf Kirchmair, D Ladurner, W BockerAbstract:Normal and hyperplastic thyroid C-cells and 14 cases of medullary thyroid carcinoma were investigated immunohistochemically with antibodies against Chromogranins A and B, secretogranin II, calcitonin and calcitonin gene-related peptide (CGRP). Normal and hyperplastic C-cells showed strong calcitonin and Chromogranin A immunoreactivity whereas CGRP, Chromogranin B and secretogranin II expression was less intense. Strong calcitonin and Chromogranin A immunoreactivity was also found in the majority of tumour cells in medullary thyroid carcinoma. The CGRP, Chromogranin B and secretogranin II staining observed was present in variable patterns. In some cases CGRP, Chromogranin B and secretogranin II could only be demonstrated in isolated tumour cells with elongated processes suggestive of neuronal differentiation of these cells. The biological function(s) of the Chromogranins/secretogranins remain(s) still unclear. There is evidence that these proteins are pro-peptides which give rise to functionally active compounds. Studies on normal C-cells and medullary thyroid carcinoma may elucidate the role of Chromogranins/secretogranins in endocrine and neuronal cells.