NEUROTRANSMITTER FUNCTION IN C. ELEGANS

神经递质通过一组参与突触囊泡胞吐和胞吞作用的共同蛋白质被释放到突触间隙中。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。这些神经递质特异性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化受体。我的实验室正在进行一项长期项目，以确定特定神经递质所需的基因产物。我们正在对秀丽隐杆线虫采用遗传方法来识别特定神经递质功能缺陷的突变体，然后克隆同源基因并使用生化分析表征蛋白质。我们建议鉴定和表征三种在神经传递中起作用的蛋白质：(1)水泡状谷氨酸转运蛋白，目前尚未表征；(2)由unc-46基因编码的水泡状GABA转运蛋白的潜在辅助蛋白；(3)由exp-1基因编码的新型兴奋性GABA受体。这些研究可能直接导致鉴定这些蛋白质的脊椎动物同源物。最终，这些实验将使我们更好地了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，并导致开发新的和更具体的药物，这些药物作用于个体神经递质系统。

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.