Chapter 5 - Novel Cell Surface Targets for the Plasminogen Activating System in the Brain: Implications for Human Disease

Abstract

The plasminogen (Pg) activator system plays an important role in the central nervous system (CNS), including processes of neuronal migration, neurite outgrowth, and neuronal plasticity. Pg and tissue-type plasminogen activator (t-PA) are primarily involved in fibrinolysis, however, they also play critical nonfibrinolytic functions in the CNS. Activation of Pg in the CNS is stimulated by unique cell surface protein complexes. One of such complexes involves the voltage-dependent anion channel 1 (VDAC1) in association with the Glucose Regulated Protein 78,000 (GRP78), t-PA, and Pg. VDAC1 is localized both at the mitochondrial and cell plasma membranes. In the mitochondria, VDAC1 transports ions, cholesterol, and metabolites across the outer mitochondrial and participates in the release of mitochondrial proapoptotic proteins to the cytosol. In cell plasma membranes, VDAC1 participates in the maintenance of redox homeostasis in normal cells and the promotion of anion efflux in apoptotic cells. VDAC and GRP78 are major players in the physical association between the endoplasmic reticulum (ER) and mitochondria which enables highly efficient transmission of Ca2+ from the ER to mitochondria under both physiological and pathological conditions. GRP78 associates with VDAC1 both at the outer mitochondrial and plasma membranes. The brain is an organ devoid of fibrin, a protein essential for efficient Pg activation, however, GRP78 and VDAC mimic fibrin to enhance the activation of locally synthesized Pg and t-PA. These functions make VDAC1 and GRP78 a point of convergence for a large variety of cell survival and death signals.