The Extended Granin Family: Structure, Function, and Biomedical Implications

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. (Endocrine Reviews 32: 755-797, 2011) I. Introduction A. Regulated secretion B. Secretory granule biogenesis and content II. Structural Comparison of Granins A. Why consider the granins as members of a structurally and functionally related family? B. The original granin proteins: CgA and CgB C. Additional members of the granin family: SgII, SgIII, 7B2, NESP55, VGF, and proSAAS III. Sorting and Granulogenesis A. Biosynthesis and intracellular trafficking of granins B. Mechanisms of granin sorting into regulated secretory pathway granules C. Function of granins in dense core secretory granule biogenesis D. Regulation of DCG biogenesis by the CgA-derived peptide serpinin E. Regulation of intracellular calcium stores by granin proteins in DCG IV. Granin-Derived Peptides and Their Mechanisms of Action in Endocrine and Neuroendocrine Systems A. Regulation of glucose balance: CgA peptide pancreastatin B. Regulation of feeding and energy expenditure: VGF NERP and C-terminal peptides C. Regulation of gastrointestinal function: VGF peptide TLQP-21 D. Regulation of prohormone convertase activity: 7B2 and proSAAS