Abstract
This study examined the signal transduction pathways involved in thrombin-induced neuroprotection and compares these results with those of a similar study of thrombin-induced neuronal death. In thrombin-induced protection of astrocytes from hypoglycemia, pretreatment of astrocytes with tyrosine or serine/threonine kinase inhibitors, cytochalasin D, or exoenzyme C3, a potent inhibitor of the small GTPase RhoA, attenuated thrombin-induced protection. These same inhibitors were previously shown to block thrombin-induced cell death, implying a similarity in the cell death and cell-protective pathways. Biochemical assays determined that thrombin increased available RhoA activity, although more slowly and to a lesser extent than occurs in thrombin-induced cell death. A clear difference in these pathways was revealed when a time course study of thrombin-induced cell death indicated that unlike thrombin-induced protection, cells must be exposed to thrombin for >16 h to irreversibly enter the cell death pathway. Addition of lower doses of thrombin every 24 h also induced cell death. These studies indicate that exposure of cells to micromolar concentrations of thrombin alone does not induce cell death, but the continued exposure to thrombin is required. Thus the cell death and protective pathways may share initial signaling proteins, but differences in the amplitude as well as the duration of the signal may result in different final pathways.
Highlights
Response, and as these pathways appear to be similar to pathways recently reported to be involved in the apoptosis response, how do cells distinguish between these signals?
Pharmacological Characterization of the Signal Transduction Cascade Underlying Thrombin-induced Neuroprotection: Involvement of Tyrosine Kinases, Serine/Threonine Kinases, and the Actin Cytoskeleton—PAR-1 receptor activation can result in induction of a variety of different second messengers, including hydrolysis of phosphoinositides, calcium mobilization, and activation of heterotrimeric G-proteins, tyrosine kinases, and monomeric G-proteins [26]
We presented findings indicating the involvement of tyrosine and serine/threonine kinases and the small GTP-binding protein RhoA in the signal transduction pathways of thrombininduced protection of astrocytes
Summary
Response, and as these pathways appear to be similar to pathways recently reported to be involved in the apoptosis response, how do cells distinguish between these signals?. The Available RhoA Activity Is Increased by Thrombin during Thrombin Protection from Hypoglycemia—The small GTPbinding protein RhoA has previously been linked to thrombininduced cellular responses, including neurite retraction in NEI-115 neuroblastoma cells [41] and, most recently, thrombin-induced apoptosis in astrocytes and hippocampal neurons [6].
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