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.
| Miles, Lindsey A; Lighvani, Shahrzad; Baik, Nagyung et al. (2014) New insights into the role of Plg-RKT in macrophage recruitment. Int Rev Cell Mol Biol 309:259-302 |
| Gingles, N A; Bai, H; Miles, L A et al. (2013) Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo. J Thromb Haemost 11:1707-15 |
| Miles, Lindsey A; Parmer, Robert J (2013) Plasminogen receptors: the first quarter century. Semin Thromb Hemost 39:329-37 |
| Felez, Jordi; Jardi, Merce; Fabregas, Pere et al. (2012) Monoclonal antibodies against receptor-induced binding sites detect cell-bound plasminogen in blood. Blood 120:678-81 |
| Miles, Lindsey A; Lighvani, Shahrzad; Baik, Nagyung et al. (2012) The plasminogen receptor, Plg-R(KT), and macrophage function. J Biomed Biotechnol 2012:250464 |
| Bai, Hongdong; Nangia, Samir; Parmer, Robert J (2012) The plasminogen activation system and the regulation of catecholaminergic function. J Biomed Biotechnol 2012:721657 |
| Bai, Hongdong; Baik, Nagyung; Kiosses, William B et al. (2011) The novel plasminogen receptor, plasminogen receptor(KT) (Plg-R(KT)), regulates catecholamine release. J Biol Chem 286:33125-33 |
| Jiang, Qijiao; Gingles, Neill A; Olivier, Marc A et al. (2011) The anti-fibrinolytic SERPIN, plasminogen activator inhibitor 1 (PAI-1), is targeted to and released from catecholamine storage vesicles. Blood 117:7155-63 |
| Lighvani, Shahrzad; Baik, Nagyung; Diggs, Jenna E et al. (2011) Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT. Blood 118:5622-30 |
| Han, Jaena; Baik, Nagyung; Kim, Kee-Hwan et al. (2011) Monoclonal antibodies detect receptor-induced binding sites in Glu-plasminogen. Blood 118:1653-62 |
Showing the most recent 10 out of 30 publications
