MOLECULAR MECHANISMS OF SIGNAL TRANSDUCTION IN RETINA

描述（改编自申请人的摘要）：在视网膜，专门 突触传递由光刺激引起的分级超极化， 光感受器到二级神经元，即，两极和水平 细胞在这些带状突触中，神经递质谷氨酸持续地 在黑暗中释放并刺激突触后细胞上的谷氨酸受体 (AMPA水平和关闭双极细胞上的/红藻氨酸盐型受体;打开双极细胞上的mGluR 6 双极细胞）。代谢型谷氨酸受体mGluR 8，我们最近 克隆，存在于感光细胞末端。我们假设， 在海马体和嗅觉系统中，它可能提供了一个 谷氨酸释放的负反馈调节。我们最近生成了 其中mGluR 8已经被同源的 重组我们将使用这些动物，以及表达 mGluR 8或突变体mGluR 8以解决以下特定目的：（1）是否 光感受器突触和视网膜发育因缺乏 缺乏这种受体的转基因动物中的mGluR 8;（2）什么信号 转导途径将mGluR 8激活与 细胞内钙水平和谷氨酸释放;（3）什么 控制mG 1uR 8定位于轴突末梢;以及（4）这是如何 提出了mGluR 8对感光细胞谷氨酸的负反馈调节 释放塑造双极细胞的光反应。这一目标将在 与Rowland Taylor（约翰科廷医学研究学院）合作， 是目前唯一能够进行这种实验的人。拟议规例 mGluR 8在光感受器带状突触的突触传递是 可能对视觉很重要，因为在这个突触处，膜电位 由光转导产生的变化被转换成 神经递质释放

DESCRIPTION (Adapted from applicant's abstract): In the retina, specialized synapses transmit the graded hyperpolarization induced by light stimuli in photoreceptors to the second order neurons, i.e., and bipolar and horizontal cells. At these ribbon synapses, the neurotransmitter glutamate is continuously released in the dark and stimulates glutamate receptors on postsynaptic cells (AMPA/kainate-type receptors on horizontal and OFF-bipolar cells; mGluR6 on ON bipolar cells). The metabotropic glutamate receptor mGluR8, which we recently cloned, is present in the photoreceptor terminal. We hypothesize that there, as in the hippocampus and olfactory system, it may be providing a negative-feedback regulation of glutamate release. We recently generated transgenic mice in which mGluR8 has been inactivated by homologous recombination. We will use these animals, as well as cell lines that express mGluR8 or mutant mGluR8 to address the following specific aims: (1) whether photoreceptor synapses and retinal development are altered by the absence of mGluR8 in transgenic animals lacking this receptor; (2) what the signal transduction pathway is linking mGluR8 activation to a modulation of intracellular calcium level and, presumably, glutamate release; (3) what controls the localization of mG1uR8 to axon terminals; and (4) how this proposed negative-feedback regulation of mGluR8 on photoreceptor glutamate release shapes the light responses of bipolar cells. This aim will be done in collaboration with Rowland Taylor (John Curtin School of Medical Research) who is currently uniquely able to perform such experiments. The proposed regulation of synaptic transmission by mGluR8 at the photoreceptor ribbon synapse is likely to be important for vision since at this synapse, the membrane potential changes produced by phototransduction are converted into a modulation of neurotransmitter release.