Vesicular Transporter Specificity

描述（由申请人提供）：本项目重点阐明囊状神经递质转运体上的分子位点，这些分子位点为神经递质摄取和靶向突触释放位点提供了多样性和特异性。最近，我们发现两个蛋白（VGLUT1和VGLUT2）在神经末梢的突触囊泡（ssv）上选择性表达，这些蛋白将谷氨酸转运到突触囊泡（ssv）中，定义了中枢神经系统中两类谷氨酸突触。我们现在已经分子鉴定和功能表征了第三种异构体VGLUT3，并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。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，提示这三种泡状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)确定三种异构体内在功能活动的差异，以更好地了解谷氨酸囊泡运输机制；2)确定特异性靶向变异和轴突末端的重要位点，这些位点可能提供谷氨酸突触功能容量、敏感性和可塑性的多样性。这些研究结果可能为进一步研究特定神经元在与癫痫和各种神经退行性疾病相关的谷氨酸毒性中的差异作用提供基础。

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.