Catecholamine storage vesicles and the metabolic syndrome: the role of the chromogranin A fragment pancreastatin

Abstract

Chromogranins or secretogranins (granins), present in secretory granules of virtually all neuroendocrine cells and neurones, are structurally related proteins encoded by different genetic loci: chromogranins A and B, and secretogranins II through VI. Compelling evidence supports both intracellular and extracellular functions for this protein family. Within the cells of origin, a granulogenic or sorting role in the regulated pathway of hormone or neurotransmitter secretion has been documented, especially for chromogranin A (CHGA). Granins also function as pro-hormones, giving rise by proteolytic processing to an array of peptide fragments for which diverse autocrine, paracrine, and endocrine activities have been demonstrated. CHGA measurements yield insight into the pathogenesis of such human diseases as essential hypertension, in which deficiency of the catecholamine release-inhibitory CHGA fragment catestatin may trigger sympathoadrenal overactivity as an aetiologic culprit in the syndrome. The CHGA dysglycaemic fragment pancreastatin is functional in humans in vivo, affecting both carbohydrate (glucose) and lipid (fatty acid) metabolism. Pancreastatin is cleaved from CHGA in hormone storage granules in vivo, and its plasma concentration varies in human disease. The pancreastatin region of CHGA gives rise to three naturally occurring human variants, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. These observations establish a role for pancreastatin in human intermediary metabolism and disease, and suggest that qualitative hereditary alterations in pancreastatin's primary structure may give rise to interindividual differences in glucose disposition.

Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population

“…G297S) in the dysglycemic peptide PST (an inhibitor of insulin-stimulated glucose uptake; Ref. 43) that is in strong linkage disequilibrium with the CST G364S SNP. Likewise, CST has recently been reported to increase lipolysis (triglyceride hydrolysis) and lipid mobilization in adipose tissues via its interaction with ␣2-adrenergic receptor and leptin receptor (19).…”

Differential distribution of VGF-derived peptides in the adrenal medulla and evidence for their selective modulation

“…Finally, the possibility of intracellular roles for at least some VGF-derived peptides should be mentioned, as has been shown for various chromogranins and their multiple products, involved in a long list of both intra-and extracellular regulatory mechanisms (Zhang et al 2006). …”

Molecular Mechanism for Hypertensive Renal Disease

“…5 CHGA is also a prohormone that gives rise to biologically active peptides, such as the catecholamine release inhibitor catestatin, 6 the dysglycemic peptide pancreastatin, 7,8 and the vasodilator vasostatin. 9 Previously, we found that naturally occurring human genetic variation in the 39-region of the CHGA gene was associated with autonomic BP regulation and hypertension in several human populations 10 as well as hypertensive renal disease in African Americans, 11 and it predicts the rate of chronic GFR decline in such patients.…”