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Notes: Secretogranin M (Sgll), also called chromogranin C, is an acidic tyrosine-sulfated secretory protein found in secretory granules in a wide variety of endocrine cells and neurones. Although less abundant than chromogranin A (CGA) and chromogranin B (CGB), Sgll is found in adrenal medullary chromaffin granules. In the present study we investigated the regulation of Sgll biosynthesis in bovine chromaffin cells maintained in primary culture. Cellular proteins were labelled with [35S]methionine and the heat stable chromogranin enriched fraction was isolated. Following electrophoretic separation, the 86 kDa Sgll band was identified by sequence analysis using the Edman degradation procedure. The radioactivity incorporated in the 86 kDa Sgll band was used as an index of the Sgll synthesis rate. We found that stimulation of chromaffin cells with nicotine and histamine and to a smaller extent with angiotensin II and bradykinin significantly enhanced the rate of Sgll synthesis. In contrast direct depolarization with K+ had no effect on Sgll synthesis suggesting that the raise of cytosolic calcium evoked by high K+ may not be sufficient to induce modifications in Sgll synthesis. The possible second messenger pathways involved in the control of Sgll biosynthesis were investigated by using protein kinase C and adenylate cyclase activators. We observed that 12-O-tetradecanoylphorbol 13-acetate (TPA) and forskolin increased the basal rate of Sgll synthesis. Incubation with both TPA and forskolin was required to obtain an effect comparable to that produced by nicotine or histamine suggesting that these secretagogues recruit both protein kinase C- and cyclic AMP-dependent mechanisms to stimulate Sgll synthesis. Our results indicate that within chromaffin granules, the rates of CGA, CGB and Sgll synthesis are independently regulated and suggest a close relationship between the cell secretory activity and the biosynthesis of Sgll.The biological role of Sgll is unknown but it has been suggested that the protein may function as a precursor of potentially bioactive peptides. Here we identified a Sgll derived peptide corresponding to the C-terminal residues 582–586 in the soluble core of purified chromaffin granules. This peptide was released together with catecholamines upon stimulation of cultured chromaffin cells indicating that the peptide was present within the storage complex of chromaffin granules and was not the result of some artefactual proteolytic degradation of Sgll during the course of granule purification. We propose that this peptide is a specific product of the post-translational processing of Sgll. By analogy with peptides derived from CGA and CGB, it may possess some specific biological activity that remains to be identified.