Publication Date:
2013-11-09
Description:
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. This article is protected by copyright. All rights reserved.
Print ISSN:
0022-3042
Electronic ISSN:
1471-4159
Topics:
Medicine
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