The possibility that activation of thrombin receptors in the brain can exert a neuroprotective role against ischemia or cerebral hemorrhage has recently emerged. In our laboratory, I have demonstrated the addition of low concentrations of thrombin, acting via specific receptors, can enhance the release of taurine from hypotonically-stressed human 1321N1 astrocytoma and primary cultures of rat astrocytes. Thrombin-stimulated taurine efflux is inhibited by agents known to block the volume-sensitive organic anion channel (VSOAC). Neural cell swelling often results from a lowering of plasma osmolarity, a clinical condition known as hyponatremia. A homeostatic mechanism known as regulatory volume decrease (RVD) is crucial in the central nervous system to normalize cell volume after hypo-osmotic swelling and involves the release of organic osmolytes, such as taurine, via a VSOAC. In this proposal, I plan to extend the novel observation that thrombin can enhance osmolyte release by identifying the signaling pathway(s) utilized by thrombin and evaluating the relationship between the ability of thrombin to enhance taurine release and changes in cell volume, as measured by Coulter Counter and Atomic Force Microscopy. The ability of thrombin receptors to regulate osmolyte efflux may represent a mechanism whereby RVD is enhanced. For the rational design of therapeutic agents in the treatment of brain edema, both the identification of receptors that regulate VSOAC and the elucidation of signal transduction pathways involved are essential prerequisites.
| Fisher, Stephen K; Cheema, Tooba A; Foster, Daniel J et al. (2008) Volume-dependent osmolyte efflux from neural tissues: regulation by G-protein-coupled receptors. J Neurochem 106:1998-2014 |
| Cheema, Tooba A; Fisher, Stephen K (2008) Cholesterol regulates volume-sensitive osmolyte efflux from human SH-SY5Y neuroblastoma cells following receptor activation. J Pharmacol Exp Ther 324:648-57 |
| Cheema, Tooba A; Pettigrew, Veryan A; Fisher, Stephen K (2007) Receptor regulation of the volume-sensitive efflux of taurine and iodide from human SH-SY5Y neuroblastoma cells: differential requirements for Ca(2+) and protein kinase C. J Pharmacol Exp Ther 320:1068-77 |
| Cheema, Tooba A; Ward, Caroline E; Fisher, Stephen K (2005) Subnanomolar concentrations of thrombin enhance the volume-sensitive efflux of taurine from human 1321N1 astrocytoma cells. J Pharmacol Exp Ther 315:755-63 |
