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

激素和神经递质的释放依赖于一个称为胞吐的过程，该过程涉及SNARE蛋白：靶质膜上的syntaxin 1A和SNAP-25以及囊泡膜上的VAMP。质膜上的t-SNARE的可用性被认为在控制胞吐的量中起主要作用。与Munc 18结合的Syntaxin 1A构成了不能与SNAP-25相互作用的封闭Syntaxin的“非生产性储备”池。能够从Munc 18释放Syntaxin 1A从而使其可与SNAP-25相互作用的细胞内信使被预见在增强胞吐作用中发挥主要作用-这是一种具有记忆和学习分支的过程。我们已经确定了花生四烯酸，一种发挥这一作用的信使。我们第一次能够在分子水平上操纵不同的SNARE蛋白库，这对我们理解分泌机制有直接的影响。目前很少有模型可以用来理解学习和记忆是如何在大脑中发生的。我们的研究指出了一个新的方向：存在于神经分泌细胞质膜上的SNARE蛋白的“活性”和“非生产性储备”池的数量处于动态平衡，花生四烯酸，一种能够跨突触作用的第二信使，可以修改这种平衡，导致“活性”SNARE的数量增加，从而增强由胞吐作用释放的递质激素的数量。重要的是，这项研究为分泌机制的动态观点奠定了基础，对糖尿病和神经退行性疾病等疾病的治疗具有重要意义。我们希望通过在分子水平上了解分泌细胞如何调节其分泌量，我们将能够修改这些参数，以对抗神经系统疾病。

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.