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regulate catecholamine storage and release

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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. Here, we show reciprocal actions of Chromogranin B (CHGB) on catecholamine storage (stimulation) and release (inhibition). The figure synthesizes consequences of experimental results. Within chromaffin cells, CHGB participates in assembly of catecholamine secretory vesicles, and governs their secretory capacity under nicotinic stimulation. After cleavage and release into the extracellular space, CHGB [and its peptide hCHGB[60-67](KFEVRLLR)] exerts negative feedback effects to inhibit the secretory response to acetylcholine (ACh).

Zhang K, Biswas N, Gayen JR et al., J Neurochem. 2013 Nov 8. doi: 10.1111/jnc.12527. [Epub ahead of print] 

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