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The Journal of Neuroscience, December 13, 2006, 26(50):13017-13024; doi:10.1523/JNEUROSCI.2070-06.2006
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Cellular/Molecular
Cell-Surface Actin Binds Plasminogen and Modulates Neurotransmitter Release from Catecholaminergic Cells
Lindsey A. Miles,1 Nicholas M. Andronicos,1 Nagyung Baik,1 andRobert J. Parmer2 1Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, California, 92037 and 2Department of Medicine, University of California, San Diego, and Veterans Administration San Diego Healthcare System, San Diego, California 92161
Correspondence should be addressed to Dr. Robert J. Parmer, Nephrology/Hypertension (9111-H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161. Email: rparmer{at}ucsd.edu
An emerging area of research has documented a novel role for the plasminogen activation system in the regulation of neurotransmitter release. Prohormones, secreted by cells within the sympathoadrenal system, are processed by plasmin to bioactive peptides that feed back to inhibit secretagogue-stimulated release. Catecholaminergic cells of the sympathoadrenal system are prototypic prohormone-secreting cells. Processing of prohormones by plasmin is enhanced in the presence of catecholaminergic cells, and the enhancement requires binding of plasmin(ogen) to cellular receptors. Consequently, modulation of the local cellular fibrinolytic system of catecholaminergic cells results in substantial changes in catecholamine release. However, mechanisms for enhancing prohormone processing and cell-surface molecules mediating the enhancement on catecholaminergic cells have not been investigated. Here we show that plasminogen activation was enhanced >6.5-fold on catecholaminergic cells. Carboxypeptidase B treatment decreased cell-dependent plasminogen activation by
90%, suggesting that the binding of plasminogen to proteins exposing C-terminal lysines on the cell surface is required to promote plasminogen activation. We identified catecholaminergic plasminogen receptors required for enhancing plasminogen activation, using a novel strategy combining targeted specific proteolysis using carboxypeptidase B with a proteomics approach using two-dimensional gel electrophoresis, radioligand blotting, and tandem mass spectrometry. Two major plasminogen-binding proteins that exposed C-terminal lysines on the cell surface contained amino acid sequences corresponding to ß/
-actin. An anti-actin monoclonal antibody inhibited cell-dependent plasminogen activation and also enhanced nicotine-dependent catecholamine release. Our results suggest that cell-surface-expressed forms of actin bind plasminogen, thereby promoting plasminogen activation and increased prohormone processing leading to inhibition of neurotransmitter release.
Key words: chromaffin cell; plasminogen; release; actin; nicotinic; catecholamine
Received May 15, 2006; revised Nov. 3, 2006; accepted Nov. 4, 2006.
Correspondence should be addressed to Dr. Robert J. Parmer, Nephrology/Hypertension (9111-H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161. Email: rparmer{at}ucsd.edu
This article has been cited by other articles:
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[Abstract] [Full Text] [PDF]
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