Chromogranin A (CgA) is the major soluble protein in the core of catecholamine storage vesicles. Recent evidence suggests that CgA functions as a prohormone and contains in its primary structure the sequences for pancreastatin, which suppresses islet beta cell secretion, and chromostatin, which suppresses secretagogue-stimulated catecholamine release. However, the protease(s) responsible for release of these bioactive peptides and processing of CgA in vivo have not been identified. This proposal seeks to investigate the interaction between CgA and the plasminogen/plasmin protease system, the major enzyme system in fibrinolysis. We have performed preliminary studies suggesting that: 1) CgA is a substrate for plasmin; 2) cleavage of CgA by plasmin liberates bioactive peptide fragments which modulate (inhibit) secretagogue- stimulated catecholamine release; 3) plasminogen (as well as its activator t-PA) binds with high capacity to chromaffin cells; and 4) plasminogen and t-PA are expressed in chromaffin cells. Thus, the hypothesis to be tested in this proposal is that chromaffin cells can co-localize plasminogen and t-PA for local generation of plasmin in the environment into which CgA is secreted, providing a mechanism for processing CgA into bioactive peptides. These interactions between CgA and plasmin(ogen) represent a heretofore unrecognized relationship between catecholaminergic and fibrinolytic pathways and a novel system which may have a dramatic impact upon catecholamine secretion. Since efferent sympathetic/catecholaminergic function is a crucial determinant of normal cardiovascular and renal physiology, the results will have broad implications for diseases characterized by abnormal sympathetic activity such as hypertension, renal insufficiency (through renal sympathetic nerves), congestive heart failure, cardiac arrhythmias, orthostatic hypotension, and pheochromocytoma. In addition, and in more general terms, the studies seek to understand a potentially new role for plasminogen/plasmin that is, as a prohormone processing protease in the neuroendocrine system.
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