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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.

The chromogranins comprise a class of acidic proteins that are secreted from large dense core vesicles and expressed in neuronal and endocrine tissues. We describe here the molecular characterization of NESP55 (neuroendocrine secretory protein of M r 55,000), a novel member of the chromogranins. Several NESP55 cDNA clones were isolated from bovine chromaffin cell libraries. The cDNA sequence of NESP55 totals 1499 nucleotides. All of the clones that were isolated contained in their 3-untranslated mRNA a sequence that was homologous to exon 2 of the G-protein G s ␣. The open reading frame encodes for an acidic and hydrophilic protein of 241 amino acids with a predicted molecular mass of 27,494 Da. An antiserum directed against the C terminus of NESP55 labeled a band of M r 55,000 with an acidic pI ranging from 4.4 to 5.2 in one-and two-dimensional immunoblots of secretory proteins from chromaffin granules. NESP55 is localized within the cell to the large dense secretory vesicles and is expressed, apart from the adrenal medulla, in the anterior and posterior pituitary and various regions of the brain. For the physiological function, one interesting factor has emerged. NESP55 is proteolytically processed within the chromaffin granule to smaller peptides that might be physiologically active. One tetrapeptide, Leu-Ser-Ala-Leu (LSAL), present in the NESP55 sequence and flanked by arginine residues suitable for cleavage by prohormone convertases, has been identified recently as an endogenous antagonist of the serotonergic 5-HT 1B receptor subtype. Alterations in the serotonergic system are thought to play an important role in mental disorders, especially depression, and might be related to abnormal ethanol consumption. It is tempting to speculate that increased expression of NESP55 or its proteolytically derived peptide LSAL might contribute to the pathophysiology of the serotonergic transmission.Synaptic transmission is mediated via exocytotic release of neurotransmitters from presynaptic terminals followed by binding of these substances to specific receptors located on the postsynaptic plasma membrane. In addition to classical neurotransmitters like glutamate, ␥-aminobutyric acid, acetylcholine, noradrenaline, dopamine, or serotonin, several peptides are secreted. These peptides are stored together with neurotransmitters in specialized vesicular containers, i.e. large dense core vesicles. In recent years we characterized the content of large dense core vesicles to a great extent with the intention of identifying novel peptidergic substances involved in chemical signaling across neurons (1, 2). The majority of the proteins found in the content of large dense core vesicles have an acidic pI of 4 -5 and were collectively named chromogranins (3). These proteins typically consist of 200 -700 amino acids with glutamic acid as the most abundant individual amino acid. In their primary amino acid sequence, multiple pairs of consecutive basic amino acid residues known as cleavage sites for trypsin-like endoproteases are present...

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