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 catecholamine-storage vesicles and is also distributed widely in secretory vesicles throughout the neuroendocrine system. CgA contains the sequences for peptides that modulate catecholamine release, but the proteases responsible for the release of these bioactive peptides from CgA have not been established. We show here that the major fibrinolytic enzyme, plasmin, can cleave CgA to form a series of large fragments as well as small trichloroacetic acid-soluble peptides. Peptides generated by plasmin-mediated cleavage of CgA significantly inhibited nicotinic cholinergic stimulation of catecholamine release from PC12 cells and primary bovine adrenal chromaffin cells. We also show that the zymogen, plasminogen, as well as tissue plasminogen activator bind saturably and with high capacity to catecholaminergic (PC12) cells. Occupancy 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 results 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 secreted to generate peptides which may regulate neuroendocrine secretion. Interactions between CgA and plasmin(ogen) define a previously unrecognized autocrine/paracrine system that may have a dramatic impact upon catecholamine secretion.
Parmer
R J
RJ
Department of Medicine, University of California, and Veterans Administration Medical Center, San Diego, California 92161, USA. rparmer@ucsd.edu
Mahata
M
M
Gong
Y
Y
Mahata
S K
SK
Jiang
Q
Q
O'Connor
D T
DT
Xi
X P
XP
Miles
L A
LA
D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D002417:Cattle; D002450:Cell Communication; D019439:Chromaffin Cells / Q000378:metabolism; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D005342:Fibrinolysis; D008239:Lysine / Q000031:analogs & derivatives; D009490:Neurosecretory Systems / Q000378:metabolism; D016716:PC12 Cells; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D002395:Catecholamines; D053379:Chromogranin A; D002864:Chromogranins; D011978:Receptors, Nicotinic; C506153:chromogranin A, rat; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D008239:Lysine