Brief description:

Nitric oxide (NO) is a diatomic gas that has traditionally been viewed, particularly in the context of chemical fields, as a toxic, pungent gas that is the product of ammonia oxidation. However, NO has been associated with many biological roles including cell signalling, macrophage cytotoxicity and vasodilation. More recently, a model for NO efflux has been proposed where NO is regulated in the form of dinitrosyl-dithiol-iron-complexes (DNICs), which are much less toxic and have a significantly greater half-life than free NO. My laboratory has previously examined this hypothesis in tumour cells, demonstrating that DNICs are transported and stored by multi-drug resistant related protein 1 (MRP1) and glutathione-s-transferase P1 (GST P1). A crystal structure for DNIC-GST P1 complexes has been solved that demonstrates that a tyrosine residue in GST P1 is responsible for binding DNICs. Considering NO’s roles in vasodilation and many other processes, a physiological model of NO transport and storage would be invaluable in understanding NO physiology and pathophysiology. This project aims to assess if GST P1 and other GST family members (GST A and M) form an integrated system of NO storage and transport together with MRP1 in macrophages, endothelial cells, and hepatoma cells. These aims collectively serve to test the hypothesis that NO is not freely diffusible in cells but is rather stringently regulated by interacting with proteins to enable transport and storage.