Deciphering the molecular steps leading to the potentiation of neuronal exocytosis by arachidonic acid

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Release of hormones and neurotransmitters relies on a process called exocytosis which involves SNARE proteins: syntaxin1A and SNAP-25 on the target plasma membrane and VAMP on the vesicular membrane. Availability of the t-SNARE on the plasma membrane is believed to play a major role in controlling the amount of exocytosis. Syntaxin1A bound to Munc18 constitute an 'unproductive-reserve' pool of closed Syntaxin that cannot interact with SNAP-25. Intracellular messengers capable of releasing Syntaxin1A from Munc18 thereby making it available to interact with SNAP-25, are foreseen to play a major role in potentiating exocytosis - a process with ramification for memory and learning. We have identified arachidonic acid, a lipidic messenger which fullfil this role. For the first time we are in a position to manipulate at the molecular level different pools of SNARE proteins with direct implications for our understanding of the mechanism of secretion. Very few models are currently available to understand how learning and memory occur in the brain. Our research points to a new direction: the amount of 'active' and 'unproductive-reserve' pools of SNARE proteins present on the plasma membrane of neurosecretory cells are in dynamic equilibrium and arachidonic acid, a second messenger capable of trans-synaptic action, can modify this equilibrium resulting in an increase of the amount of 'active' SNARE thereby potentiating the amount of transmitter-hormone released by exocytosis. Importantly, this research lays the basis for a dynamic view of the secretory mechanism with important implications for treatment of diseases such as diabetes and neurodegenerative diseases. Our hope is that by understanding at the molecular level how secretory cells regulate the amount of their secretion, we will be in a position to modify these parameters in order to counteract illnesses of the nervous system.