Review articleGranin-derived peptides
Introduction
The granin family of uniquely acidic proteins comprises three main members, i.e. chromogranin (CgA), chromogranin B (CgB) and secretogranin II (SgII). These proteins are expressed in central and peripheral neurons and in neuronal and non-neuronal endocrine tissues (see reviews by Huttner et al., 1991; Winkler and Fischer-Colbrie, 1992, Fischer-Colbrie et al., 1995, Helle, 2004, Montero-Hadjadje et al., 2008, Borges et al., 2013). They are also present in cells and tissues such as in polymorphonuclear neutrophils (Helle, 2010a), the myocardium (Yoo, 2012), a variety of tumors (D’Herbomez et al., 2016) as well as in saliva (Mizuhashi et al., 2015, Kogawa et al., 2016) and in the circulation (Yang et al., 2015). The human CgA, CgB and SgII are targeted by a range of intra- and extracellular proteases, cleaving at multiple sites in the amino acid sequences, e.g. at 12, 18 and 9 pairs of basic amino acids in CgA, CgB and SgII, respectively (Huttner et al., 1991, Portela-Gomes et al., 2010). The first granin–derived peptide was described in 1987 when the insulin release inhibiting peptide pancreastatin was identified as the midsection of CgA (Fig. 1) (Huttner and Benedum, 1987, Schmidt et al., 1988), making it likely that not only CgA, but also CgB (Fig. 2) and SgII (Fig. 3) might serve as prohormones for biologically active peptides (Eiden, 1987).
The functional roles of the granin-derived peptides are diverse. Not only do they play important functions in the formation of secretory granules (Chanat and Huttner, 1991, Gerdes and Glombik, 2000, Montero-Hadjadje et al., 2008) and in costorage and corelease of catecholamines (Banks and Helle, 1965, Blaschko et al., 1967, Borges et al., 2013, Estevéz-Herrera et al., 2016); they also exert regulatory effects on the protection against microbial invasions (Metz-Boutigue et al., 1998), on the integrity of the vasculature (Ferrero et al., 2004), on myocardial contractility (Angelone et al., 2008), on angiogenesis in wound healing (Crippa et al., 2013) and in tumors (Bianco et al., 2016a, Bianco et al., 2016b, Curnis et al., 2016) as well as in inflammatory diseases (Zhang et al., 2009). Although both CgA and CgB each play significant roles in the accumulation and exocytosis of the catecholamines, the lack of both proteins in double knockout mice reduces vesicular amine content to half while other proteins, such as fibrinogen, appear to compensate for the absence of the granins in the secretory pathway (Diaz-Vera et al., 2012). Moreover, the lack of both granins markedly reduced responses to stress and exerted hypersensitivity to insulin as well as increases in aggressive behaviour (Pereda et al., 2015).
Section snippets
Processing of granins by intra- and extracellular proteases
The mammalian prohormone convertases (PCs) are serine proteinases related to the bacterial-subtilisin/yeast-kexin PC family (Seidah and Chretien, 1999). Importantly, PC1/3 and PC2, cleaving at single or pairs of basic amino acids, are specific for intragranular processing in neuroendocrine tissues (Eskeland et al., 1996, Udupi et al., 1999, Doblinger et al., 2003, Von Eggelkraut-Gottanka and Beck-Sickinger, 2004). In addition, also furin and cathepsin L are colocalized with granins in secretory
The CgA-derived peptides
As discussed above and illustrated in Fig. 1, CgA is subject to an extensive degree of intra- and extracellular proteolytic processing by cleavage at multiple dibasic sites, notably at the N- and C-terminal regions (Metz-Boutigue et al., 1993).
CgB-derived peptides
At the N-terminus of CgB (Fig. 2) the cysteine loop-containing peptide CgB1–41 (Russell et al., 1994) was shown to inhibit parathormone release analogous to the VS-I-derived CgA1–40 (Fig. 1). BAM-1745 (bCgB547–560) was the first peptide to be isolated from the C-terminal side (Flanagan et al., 1990). Soon thereafter the antimicrobial secretolytin (CgB614–626) was reported (Strub et al., 1995). Moreover, a BAM-like peptide PE-11 (rCgB552–562) in the rat brain (Krösen et al., 1996) appears also
Sg II-derived peptides
SgII, comprising 613, 617 and 619 amino acid residues in the bovine, human and rat homolouges (Fig. 3), is a member of the tyrosine-sulphated granin family (Gerdes et al., 1989, Huttner et al., 1991). Yet, processing has so far generated only one biologically active peptide, i.e. the 33 residue long peptide secretoneurin (SN, SgII154–186), the name reflecting its relative abundance in neuronal tissues (Kirchmair et al., 1993, Kirchmair et al., 1994). SgII was first localized in normal rat
Granin peptides in a sense organ
The only sense organ yet to be explored for several of the granin-derived peptides is the eye. Not only the biologically active peptides, such as the CgA-derived CST and the SgII-derived SN, but also the inert peptides including the CgA-derived fragments WE-14, GE-25 and the CgB peptide PE-11, have provided valuable information on the distribution of granin-positive nerve fibers and cell bodies in ocular tissues. All these peptides are present in the retina and also in tissues innervated by the
Comparison of effects of VS-I, CST and SN
The literature reviewed above on the functional effects of granin-derived peptides points to particular impacts of a few, namely the CgA-derived VS-I and CST and the SgII derived SN. As summarized in Table 2, VS-I appears to have opposite effects to those of CST and/or SN on several vital functions, such as cell adhesion, chemotaxis and proliferation and on angiogenesis and endothelial integrity under normal and/or pathological conditions. Yet, only VS-I and CST appear to exert cardioprotection
Summing up and concluding remarks
Data accumulated since the mid 1980s are consistent with the concept of the three main granins, CgA, CgB and SgII serving as prohormones for a wide range of biologically active peptides, some of them with physiological and/or pathophysiological significance. Proteolytic cleavage occurs in species- and tissue-specific patterns, intracellularly and extracellularly, and the resulting granin-derived peptides are widely distributed, also in species- and tissue-specific patterns. For example, in a
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