Abstract
Chromogranin A (CgA) is a prohormone and granulogenic factor in endocrine and neuroendocrine tissues, as well as in neurons, and has a regulated secretory pathway. The intracellular functions of CgA include the initiation and regulation of dense-core granule biogenesis and sequestration of hormones in neuroendocrine cells. This protein is co-stored and co-released with secreted hormones. The extracellular functions of CgA include the generation of bioactive peptides, such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin. CgA knockout mice (Chga-KO) display: (i) hypertension with increased plasma catecholamines, (ii) obesity, (iii) improved hepatic insulin sensitivity, and (iv) muscle insulin resistance. These findings suggest that individual CgA-derived peptides may regulate different physiological functions. Indeed, additional studies have revealed that the pro-inflammatory PST influences insulin sensitivity and glucose tolerance, whereas CST alleviates adiposity and hypertension. This review will focus on the different metabolic roles of PST and CST peptides in insulin-sensitive and insulin-resistant models, and their potential use as therapeutic targets.
Highlights
The human chromogranin A gene encodes a 439-amino-acid mature protein of approximately 48–52 kDa with a coiled-coil structure [1,2,3,4,5,6]
Using ligand affinity chromatography with biotinylated human PST as “bait” on a murine liver homogenate, we found that PST interacts in a pH-dependent fashion with glucose-regulated protein 78 (Grp78) [78]
These results indicate that a major hepatic target of PST is the adaptive unfolded protein response (UPR) chaperone Grp78 and that ATPase activity associated with Grp78 is involved in the suppression of glucose production by attenuating G6pc expression [78]
Summary
The human chromogranin A (gene, CHGA; protein, CgA) gene encodes a 439-amino-acid mature protein of approximately 48–52 kDa with a coiled-coil structure [1,2,3,4,5,6]. CgA has 8–10 dibasic sites and is proteolytically cleaved by prohormone convertases [25,26,27], cathepsin L [28], plasmin [29, 30], and kallikrein [31], generating biologically active peptides including the dysglycemic peptide pancreastatin (PST) (CgA250–301) [32, 33]; WE14 (hCgA324–337) which acts as the antigen for highly diabetogenic CD4+ T cell clones [34,35,36,37,38]; the vasodilating, antiadrenergic, and antiangiogenic peptide vasostatin 1 (CgA1–76) [39,40,41,42,43]; the antiadrenergic, antihypertensive, antibacterial, proangiogenic, and antiobesigenic peptide catestatin (CST) (CgA352–372) [44,45,46,47,48,49,50,51,52,53,54,55,56]; and the proadrenergic peptide serpinin (CgA402–439) [57, 58] PST increases nitric oxide (NO) levels in PST inhibition of GSIS
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