Cellular and molecular mechanisms involved in the regulation of group IVA phospolipase A2

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Arachidonic acid is fatty acid mainly found in animals. It plays critical roles in many processes, from fever to reproduction. It is so important that animals that can't make it, such as the cat, are obligatory carnivorous and then get the arachidonic acid from the meat they eat. Humans can however make it from vegetable oil containing linoleic acid. In our body, arachidonic acid is hidden within our cell walls. Special proteins named phospholipases A2 are responsible for providing arachidonic acid to our cells. Among the phospholipases A2 family, the cytosolic phospholipase A2 is very important, probably because it is found everywhere in our body. Thus, understanding how the cytosolic phospholipase A2 works is very helpful in order to understand the physiological mechanisms by which life itself is sustained. We reasonably understand how the cytosolic phospholipase A2 releases arachidonic acid. However, we do not really know how the cytosolic phospholipase A2 stops releasing arachidonic acid. This is very important because not enough or too much arachidonic acid can be lethal. Our research program aims at understanding how the cytosolic phospholipase A2 stops releasing to arachidonic acid. In this regard, we are proposing to define 2 ways by which the activity of cytosolic phospholipase A2 is turned down. The first way implies a direct modification of the cytosolic phospholipase A2 by adding a phosphate group. This likely leads to a significant decrease in arachidonic acid release. The second way involves arachidonic acid itself, which might induce the cytosolic phospholipase A2 to stop releasing it. Such a retroactive inhibition has never been documented. We were able to engineer the cytosolic phospholipase A2 in a pure form and can therefore perform many tests on the latter. We thus anticipate to define, using biochemistry molecular biology techniques, two important stop signals by which the activity of the cytosolic phospholipase A2 is turned off. The benefits are immense as 1) it will provide key aspects on how arachidonic acid is released and 2) it will train highly qualified personnel in the field of biochemistry and mass spectrometry of lipids, a research area that is poorly represented among the Canadian scientific community. In conclusion, this project will provide important insights on the regulation of the cytosolic phospholipase A2, notably about its interaction with the membranes. It will also provide useful data for the understanding of lipid mediator biosynthesis and their role in physiology and might define arachidonic acid as a central regulator of cytosolic phospholipase A2 release.