Molecular Mechanisms of Neurotransmitter Release

Akefe, Isaac O, Osborne, Shona L, Matthews, Benjamin, Wallis, Tristan P, Meunier, Frédéric A, Akefe, Isaac O., Osborne, Shona L., Wallis, Tristan P., Meunier, Frédéric A.

In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.