NEUROTRANSMITTER FUNCTION IN C. ELEGANS

神经递质通过一组共同的蛋白质释放到突触裂隙中，这些蛋白质参与突触小泡的胞吐和内吞作用。相比之下，某些突触蛋白必须根据每种特定神经递质的需要进行调整。这些神经递质特有的功能包括生物合成酶、跨囊泡和质膜转运的转运体，以及突触后表面的特殊受体。我的实验室参与了一个长期项目，以确定特定神经递质所需的基因产物。我们正在线虫秀丽线虫中采用遗传学的方法来鉴定一种特定神经递质功能缺陷的突变体，然后我们克隆同源基因并使用生化分析来鉴定蛋白质。我们建议鉴定和鉴定三种在神经传递中起作用的蛋白质：(1)囊泡型谷氨酸转运蛋白，(2)UNC-46基因编码的囊泡型GABA转运蛋白的潜在辅助蛋白；(3)由EXP-1基因编码的新的兴奋性GABA受体。这些研究很可能直接导致鉴定这些蛋白质的脊椎动物同源物。最终，这些实验将导致更好地理解这些蛋白质的分子结构如何赋予它们的功能特性。最终，这些研究可能有助于解释神经活性药物的分子行为，并导致作用于单个神经递质系统的新的、更具体的药物的开发。

Neurotransmitters are released into the synaptic cleft using a common set of proteins involved in synaptic vesicle exocytosis and endocytosis. By contrast, certain synaptic proteins must be tailored to the needs of each specific neurotransmitter. These neurotransmitter-specific functions include biosynthetic enzymes, transporters for translocation across vesicular and plasma membranes, and specialized receptors on the postsynaptic surface. My laboratory is engaged in a longterm project to identify the gene products required by specific neurotransmitters. We are taking a genetic approach in the nematode Caenorhabditis elegans to identify mutants defective for the functions of a specific neurotransmitter, we then clone the cognate genes and characterize the proteins using biochemical assays. We propose to identify and characterize three proteins which function in neurotransmission: (1) the vesicular glutamate transporter, which as yet, remains uncharacterized, (2) a potential ancillary protein to the vesicular GABA transporter encoded by the unc-46 gene, (3) a novel excitatory GABA receptor encoded by the exp-1 gene. These studies are likely to result directly in the identification of vertebrate homologs of these proteins. Eventually, these experiments will lead to a better understanding of how the molecular structures of these proteins confer their functional properties. Ultimately, these studies might help explain the molecular behavior of neuroactive drugs and lead to the development of new and more specific pharmaceuticals which act on individual neurotransmitter systems.