Processing of chromogranin A by plasmin provides a novel mechanism for regulating catecholamine secretion

Chromogranin A (CgA) is the major soluble protein in the core of catecholam ine-storage vesicles and is also distributed widely in secretory vesicles t hroughout the neuroendocrine system. CgA contains the sequences for peptide s that modulate catecholamine release, but the proteases responsible for th e release of these bioactive peptides from CgA have not been established. W e show here that the major fibrinolytic enzyme, plasmin, can cleave CgA to form a series of large fragments as well as small trichloroacetic acid-solu ble peptides. Peptides generated by plasmin-mediated cleavage of CgA signif icantly inhibited nicotinic cholinergic stimulation of catecholamine releas e from PC12 cells and primary bovine adrenal chromaffin cells. We also show that the zymogen, plasminogen, as well as tissue plasminogen activator bin d saturably and with high capacity to catecholaminergic (PC12) cells. Occup ancy of cell surface binding sites promoted the cleavage of CgA by plasmin. Positive and negative modulation of the local cellular fibrinolytic system resulted in substantial alterations in catecholamine release. These result s suggest that catecholaminergic cells express binding sites that localize fibrinolytic molecules on their surfaces to promote plasminogen activation and proteolytic processing of CgA in the environment into which CgA is secr eted to generate peptides which may regulate neuroendocrine secretion. Inte ractions between CgA and plasmin(ogen) define a previously unrecognized aut ocrine/paracrine system that may have a dramatic impact upon catecholamine secretion.