Chromogranin A as a Crucial Factor in the Sorting of Peptide Hormones to Secretory Granules

Abstract

Chromogranin A (CgA) is a soluble glycoprotein stored along with hormones and neuropeptides in secretory granules of endocrine cells. In the last four decades, intense efforts have been concentrated to characterize the structure and the biological function of CgA. Besides, CgA has been widely used as a diagnostic marker for tumors of endocrine origin, essential hypertension, various inflammatory diseases, and neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer's disease. CgA displays peculiar structural features, including numerous multibasic cleavage sites for prohormone convertases as well as a high proportion of acidic residues. Thus, it has been proposed that CgA represents a precursor of biologically active peptides, and a "granulogenic protein" that plays an important role as a chaperone for catecholamine storage in adrenal chromaffin cells. The widespread distribution of CgA throughout the neuroendocrine system prompted several groups to investigate the role of CgA in peptide hormone sorting to the regulated secretory pathway. This review summarizes the findings and theoretical concepts around the molecular machinery used by CgA to exert this putative intracellular function. Since CgA terminal regions exhibited strong sequence conservation through evolution, our work focused on the implication of these domains as potential functional determinants of CgA. Characterization of the molecular signals implicating CgA in the intracellular traffic of hormones represents a major biological issue that may contribute to unraveling the mechanisms defining the secretory competence of neuroendocrine cells.

Plasma Levels of Soluble HLA-E and HLA-F at Diagnosis May Predict Overall Survival of Neuroblastoma Patients

“…Chromogranin is a hydrophilic glycoprotein normally released by neuroendocrine cells that, upon proteolysis, produce bioactive peptides with different paracrine, autocrine, and endocrine functions [25]. In the last years, this molecule has been characterized as a promising biomarker for the diagnosis and monitoring of treatment response of gastroenteropancreatic neuroblastic tumors [10].…”

Pheochromocytoma and Multiple Endocrine Neoplasia

“…In the adrenal medulla and most sympathetic postganglionic neurons, dopamine is hydroxylated to norepinephrine. Chromogranin A (CGA) for instance, which is widely used as diagnostic marker for tumors of neuroendocrine origin, seems to have an important role for storage and release of catecholamines (Loh et al, 2004;Elias et al, 2010). Hydroxylation of dopamine to norepinephrine takes place after its active transport into granulated vesicles.…”

Chromogranin A in the early steps of the neurosecretory pathway

“…Interestingly, Taupenot et al showed that the N‐terminal end of CgA (hCgA 77–115 ) contains an amphipathic α helix (Figure a) that could be necessary, though perhaps not sufficient, for trafficking CgA into the RSP . Secondary structure prediction algorithms revealed the existence of a second α helix in the C‐terminal part of CgA (Figure a), suggesting that this region may also act as a targeting motif . It should be noted that certain processing enzymes, such as prohormone convertases PC1/3, PC2, and PC5/6, are also targeted to SG through α helices present in their C‐terminal part .…”

“…50 Secondary structure prediction algorithms revealed the existence of a second α helix in the C-terminal part of CgA (Figure 1a), suggesting that this region may also act as a targeting motif. 1 It should be noted that certain processing enzymes, such as prohormone convertases PC1/3, PC2, and PC5/6, are also targeted to SG through α helices present in their C-terminal part. [51][52][53] Moreover, carboxypeptidase E, a prohormone sorting receptor, also interacts with lipid rafts via an amphipathic α helix.…”

“…Among SG components, granins represent a family of glycoproteins including chromogranin A (CgA) which is the major constituent of SG in neuroendocrine cells. The structural features of CgA, that is, a sequence with a high proportion of acidic amino acids and a high capacity to bind calcium, allow hormone aggregation in low pH and high calcium concentration, conditions found in the TGN lumen (Figure a,b) . Furthermore, CgA sequence also displays numerous dibasic sites which are recognized by processing enzymes, leading to the formation of biologically active peptides such as vasostatin, pancreastatin, catestatin, WE‐14, and serpinin (Figure a) .…”