The Novel Plasminogen Receptor, Plasminogen ReceptorKT (Plg-RKT), Regulates Catecholamine Release

Neurotransmitter release by catecholaminergic cells is negatively regulated by prohormone cleavage products formed from plasmin-mediated proteolysis. Here, we investigated the expression and subcellular localization of Plg-R-KT, a novel plasminogen receptor, and its role in catecholaminergic cell plasminogen activation and regulation of catecholamine release. Prominent staining with anti-Plg-R-KT mAb was observed in adrenal medullary chromaffin cells in murine and human tissue. In Western blotting, Plg-R-KT was highly expressed in bovine adrenomedullary chromaffin cells, human pheochromocytoma tissue, PC12 pheochromocytoma cells, and murine hippocampus. Expression of Plg-R-KT fused in-frame to GFP resulted in targeting of the GFP signal to the cell membrane. Phase partitioning, co-immunoprecipitation with urokinase-type plasminogen activator receptor (uPAR), and FACS analysis with antibody directed against the C terminus of Plg-R-KT were consistent with Plg-R-KT being an integral plasma membrane protein on the surface of catecholaminergic cells. Cells stably overexpressing Plg-R-KT exhibited substantial enhancement of plasminogen activation, and antibody blockade of non-transfected PC12 cells suppressed plasminogen activation. In functional secretion assays, nicotine-evoked [H-3] norepinephrine release from cells overexpressing Plg-R-KT was markedly decreased (by 51 +/- 2%, p < 0.001) when compared with control transfected cells, and anti-body blockade increased [H-3] norepinephrine release from non-transfected PC12 cells. In summary, Plg-R-KT is present on the surface of catecholaminergic cells and functions to stimulate plasminogen activation and modulate catecholamine release. Plg-R-KT thus represents a new mechanism and novel control point for regulating the interface between plasminogen activation and neurosecretory cell function.