Vesicular Transporter Specificity

描述（由申请人提供）：该项目的重点是阐明囊泡神经递质转运蛋白的分子位点，这些转运蛋白为神经递质摄取和靶向突触释放位点提供多样性和特异性。最近，我们发现，两种蛋白质（VGLUT 1和VGLUT 2）的运输谷氨酸进入突触囊泡（SSV）的选择性表达的SSV在神经末梢定义两类的神经元突触在中枢神经系统。我们现在已经从分子水平上鉴定了第三种亚型VGLUT 3，并对其功能进行了表征，结果表明它在大脑中兴奋性神经元的一个新子集的静脉曲张和神经末梢中表达。在中枢神经系统中存在通路特异性、差异性和互补性兴奋性神经元，表明这三种囊泡谷氨酸转运体在神经传递中可能具有不同的生理作用。因此，下一个资助期的总体目标是：1）确定三种亚型内在功能活性的差异，以更好地理解囊泡谷氨酸转运的机制; 2）确定特异性靶向静脉曲张和轴突终末的重要位点，这些位点可能提供突触功能能力、敏感性和可塑性的多样性。这些研究的结果可能为未来的研究提供基础，这些研究可以检查特定神经元组在与癫痫发作和各种神经退行性疾病相关的谷氨酸毒性中的差异作用。

DESCRIPTION (provided by applicant): This project focuses on elucidating the molecular sites on vesicular neurotransmitter transporters that provide diversity and specificity for neurotransmitter uptake and targeting to sites of synaptic release. Recently, we showed that two proteins (VGLUT1 and VGLUT2) that transport glutamate into synaptic vesicles (SSVs) are selectively expressed on the SSVs in nerve terminals defining two classes of glutamatergic synapses in the CNS. We have now molecularly identified and functionally characterized a third isoform VGLUT3 and show that it is expressed in the varicosities and nerve terminals of a novel subset of excitatory neurons in the brain. The existence of pathway-specific, differential and complementary excitatory neurons in the central nervous system suggests that these three vesicular glutamate transporters may have distinct physiological roles in neurotransmission. Therefore, the overall goals for the next grant period are: 1) to define the differences in intrinsic functional activities of the three isoforms to better understand the mechanism of vesicular glutamate transport and 2) to identify the sites important for specific targeting to varicosities and axon terminals that might provide diversity in the functional capacity, sensitivity and plasticity of glutamatergic synapses. The results of these studies may provide the basis for future studies that can examine the differential role of specific sets of neurons in glutamate toxicity associated with seizure disorders and various neurodegenerative diseases.