Vesicular Transporter Specificity

囊泡转运蛋白特异性

• 批准号: 6876663
• 负责人: JEFFREY D ERICKSON
• 金额: $ 29.55万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876663
• 关键词: Semliki Forest virus; chimeric proteins; gene delivery system; glutamates; laboratory rat; membrane potentials; membrane transport proteins; neuronal transport; neurons; neurotransmitter transport; point mutation; protein isoforms; protein structure function; site directed mutagenesis; synaptic vesicles; tissue /cell culture; transfection

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.

描述（由申请人提供）：该项目侧重于阐明囊泡神经递质转运蛋白上的分子位点，这些位点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，我们发现两种将谷氨酸转运到突触小泡（SSV）的蛋白质（VGLUT1和VGLUT2）在神经末梢的SSV上选择性表达，定义了中枢神经系统中两类谷氨酸能突触。我们现在已经对第三种亚型 VGLUT3 进行了分子鉴定和功能表征，并表明它在大脑中新的兴奋性神经元子集的静脉曲张和神经末梢中表达。中枢神经系统中通路特异性、差异性和互补性兴奋性神经元的存在表明，这三种囊泡谷氨酸转运蛋白可能在神经传递中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动的差异，以更好地理解囊泡谷氨酸转运机制；2）确定对静脉曲张和轴突特异性靶向重要的位点可能提供谷氨酸突触功能、敏感性和可塑性多样性的末端。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症和各种神经退行性疾病相关的谷氨酸毒性中的不同作用。