title: Chromogranin B: intra- and extra-cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms.
abstract: Chromogranin B (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 electron microscopy, 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.
authors.affiliation: Departments of Medicine and Pharmacology, and Institute for Genomic Medicine (IGM), University of California at San Diego, La Jolla, California, USA; VA San Diego Healthcare System, La Jolla, California, USA.
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Nilima
authors.initials: N
authors.lastname: Biswas
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.forename: Jose Pablo
authors.initials: JP
authors.lastname: Miramontes-Gonzalez
authors.forename: C Makena
authors.initials: CM
authors.lastname: Hightower
authors.forename: Maja
authors.initials: M
authors.lastname: Mustapic
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Chun-Teng
authors.initials: CT
authors.lastname: Huang
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Hook
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Sucheta
authors.initials: S
authors.lastname: Vaingankar
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002395:Catecholamines / Q000235:genetics / Q000378:metabolism*; D002837:Chromaffin Granules / Q000235:genetics / Q000378:metabolism*; D053378:Chromogranin B / Q000502:physiology*; D045604:Extracellular Fluid / Q000502:physiology*; D006801:Humans; D007424:Intracellular Fluid / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051381:Rats
chemical_list: D002395:Catecholamines; D053378:Chromogranin B; C506140:chromogranin B, rat
keywords: adrenal; catecholamines; chromaffin; chromogranin B; hypertension