Chromogranin B: intra‐ and extra‐cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms

Abstract

CHGB is the major matrix protein in human catecholamine storage vesicles. CHGB genetic variation alters catecholamine secretion and blood pressure. Here effective Chgb protein under-expression was achieved by siRNA in PC12 cells, resulting in ~48% fewer secretory granules on EM, diminished capacity for catecholamine uptake (by ~79%), and a ~73% decline in stores available for nicotinic cholinergic-stimulated secretion. In vivo, loss of Chgb in knockout mice resulted in a ~35% decline in chromaffin granule abundance and ~44% decline in granule diameter, accompanied by unregulated catecholamine release into plasma. Over-expression of CHGB was achieved by transduction of a CHGB-expressing lentivirus, resulting in ~127% elevation in CHGB protein, with ~122% greater abundance of secretory granules, but only ~14% increased uptake of catecholamines, and no effect on nicotinic-triggered secretion. Human CHGB protein and its proteolytic fragments inhibited nicotinic-stimulated catecholamine release by ~72%. One conserved-region CHGB peptide inhibited nicotinic-triggered secretion by up to ~41%, with partial blockade of cationic signal transduction. We conclude that bi-directional quantitative derangements in CHGB abundance result in profound changes in vesicular storage and release of catecholamines. When processed and released extra-cellularly, CHGB proteolytic fragments exert a feedback effect to inhibit catecholamine secretion, especially during nicotinic cholinergic stimulation.

PICK1 is essential for insulin production and the maintenance of glucose homeostasis

“…, 2001 ), while CgB is more effective than CgA at inducing secretory granule formation in nonneuroendocrine NIH3T3 and COS-7 cells ( Huh et al. , 2003 ), thus enhancing vesicular storage and the release of catecholamines from PC12 cells ( Zhang et al. , 2014 ).…”

Quantitative proteomics of delirium cerebrospinal fluid

“…Lower CHGB expression level in knockout mice results in fewer catecholamine storage vesicles and unregulated catecholamine release into plasma. 58 Furthermore, expression of granin-related neuropeptides may be further compromised as a side effect of SERPIN protease inhibitor upregulation, potentially restricting release of neuropeptides from their granin precursors. In other words, protease inhibition may protect neurons from inflammation-related apoptosis, but as an unwanted side effect compromise granin processing.…”

Novel organelle anion channels formed by chromogranin B drive normal granule maturation in endocrine cells

“…It was proposed to participate in forming TGN proteineous aggregates and driving granule biogenesis (Takeuchi and Hosaka, 2008;Tooze, 1998). Studies of CHGB-null mice by two groups reported conflicting results regarding CHGB's role in granule biogenesis (Diaz-Vera et al, 2010; Obermuller et al, 2010;Zhang et al, 2014;Zhang et al, 2009). A mechanistic view on CHGB's intracellular functions is still unavailable.In this work we provide the first elucidation of an important intracellular function of CHGB in the regulated secretory pathway.…”