Vesicular Transporter Specificity

描述(申请人提供)：本项目致力于阐明囊泡神经递质转运体上的分子位置，为神经递质摄取和突触释放的靶点提供多样性和特异性。最近，我们发现两种将谷氨酸运输到突触小泡(SSV)的蛋白(VGLUT1和VGLUT2)选择性地表达在神经末梢的SSV上，定义了中枢神经系统中两类谷氨酸能突触。我们现在已经从分子上鉴定了第三个亚型VGLUT3，并对其功能进行了表征，结果表明，它在大脑中一个新的兴奋性神经元亚群的曲张和神经末梢中表达。中枢神经系统中存在通路特异性、差异性和互补性的兴奋性神经元，提示这三种囊泡型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，下一个授权期的总体目标是：1)确定这三种异构体内在功能活性的差异，以更好地了解囊泡谷氨酸运输的机制；2)确定可能提供谷氨酸能突触功能容量、敏感性和可塑性差异的针对曲张和轴突终末的重要部位。这些研究的结果可能为未来的研究提供基础，这些研究可以检验特定神经元组在与癫痫障碍和各种神经退行性疾病相关的谷氨酸毒性中的不同作用。

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.