Chromostatin, a chromogranin A-derived bioactive peptide, is present in human pancreatic insulin (beta) cells.

Abstract

Chromogranin A (CGA) is a secretory protein present in the adrenal medulla and in a variety ofendocrine organs. This protein may serve as precursor for pancreastatin (PST) and for other biologically active peptides. Recently, chromostatin (CST), a CGA derivative, has been identified that possesses high biological activity. The cellular distribution of CST in various endocrine organs is completely unknown. Using immunohistochemistry on plastic sections, we investigated the occurrence and cellular distribution of CST, PST, and CGA in human endocrine pancreas of healthy and diseased states and in the adrenal medulla. In the normal and diabetic pancreas, CST immunoreactivity was localized exclusively in 13 cells, which were mostly unreactive for PST and CGA. Both latter peptides were confined mainly to glucagon (a) cells. Insulinoma cells displayed strong insulin, PST, and CGA immunoreactivities, but they were faintly immunoreactive for CST or unreactive. Adrenal chromaffm cells exhibited strong immunoreactivity for CGA but lacked CST and PST immunoreactivities. Based on the peculiar distributive pattern of CST, PST, and CGA, we suggest that CGA is differentially processed in chromaffin and islet tissues and in insulinoma cells. The unique cellular localization of CST in the endocrine pancreas ofnormal and pathological conditions may indicate that CST is involved in 13-cell function.Chromogranin A (CGA) is an acidic glycoprotein originally detected in the adrenal medulla but more recently found also in a variety of peptide hormone-producing cells (see refs. 1 and 2 for review). Despite its widespread distribution, the physiological function of CGA is still largely unknown.The primary amino acid sequence of CGA, elucidated by cDNA analysis, includes several pairs of basic residues, which by analogy with other peptide hormone precursors constitute potential sites of proteolytic cleavage (3-5). Thus, it was speculated that CGA may be a putative precursor of biologically active peptides (2, 6, 7). Pancreastatin (PST), a peptide fully contained in the porcine CGA sequence (3, 7), was isolated from the porcine pancreas (8). This peptide inhibits insulin secretion (8). Moreover, tryptic digestion of CGA yielded various peptides that were able to modulate catecholamine secretion (7). Recently, chromostatin (CST) has been identified as a CGA derivative, which is localized between amino acids 124 and 143 in the bovine CGA sequence (9). In contrast to PST, CST had potent inhibitory action on chromaffin cell secretion (9).Previous studies demonstrated that pancreatic islet cells and islet cell tumors contain various CGA-derived peptides (10)(11)(12)(13)(14)(15)(16)(17). In the human pancreas, CGA has been localized mainly to glucagon (a) cells (18). The cellular distribution of PST, however, is still a matter of controversy (see ref. 19 for review), which in part may be due to species specificities (20). Data on tissue distribution of CST are completely lacking.Using specific antisera against CST, PST, and CGA, we inves...

Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

“…Secretory granules of pancreatic ␤ cells have been shown to contain several biologically active peptides including TRH, amylin, and chromogranines (25)(26)(27). These peptides are colocalized with insulin within the same secretory granules and have been suggested to possess modulatory effects on insulin secretion, but there is as yet no direct evidence to support this concept.…”

Structural and Biological Characterization of Chromofungin, the Antifungal Chromogranin A-(47–66)-derived Peptide

“…In addition, the processing of CGA and CGB has been shown to be cell-and tissue-specific (41,42), giving rise to the release of multiple peptides recovered in blood and lymph circulations but also in biological fluids such as salivary (43), synovial, milk, and cerebrospinal fluids. 40) with a unique affinity constant close to 50 nM (47).…”

Mechanisms Underlying Neuronal Death Induced by Chromogranin A-activated Microglia

“…The final CGA preparation was composed of the native 70-kDa CGA (60% of the total proteins) and smaller processed components (60 to 43 kDa), together representing 40% of the total protein, as estimated from scanned monodimensional electrophoretic profiles. Immunoblotting indicated that all protein bands were immunoreactive with specific anti-native CGA antibodies (31) and anti-CGA (124 -143) antibodies (30,31). Sequence analysis (by automatic Edman degradation on an Applied Biosystems 473A microsequencer) demonstrated that the final CGA preparation contained only CGA-derived sequences with 80% of the sequenced material containing the N-terminal sequence of CGA (LPVNS).…”