Molecular mechanisms of signal transduction in retina

描述(申请人提供)：谷氨酸是脊椎动物中枢神经系统的主要兴奋性神经递质。在视网膜中，它是从光感受器到双极细胞，再到神经节细胞的前馈通路中使用的神经递质。谷氨酸能传递是由谷氨酸受体介导的，谷氨酸受体有两大类：亲水性谷氨酸受体是配体门控离子通道。代谢性谷氨酸受体(MGluRs)是G蛋白偶联受体，其功能由第二信使通路介导。 本项目的目的是确定视网膜内网状层中G11亚型mGluRs的分布和功能。I型mGluRs被L-2-氨基-4-膦酸丁酸选择性激活，由mGluR4、-R6、-R7和-R8组成。MGluR6存在于双极细胞树突上，介导这些细胞对光的去极化反应，产生视觉通路。虽然另一类mGluRs-Ill mGluRs在大脑中广泛表达，表明它们可能参与了许多病理过程，但它们在视网膜中的确切分布和功能尚不清楚。G11 mGluRs目前作为治疗药物的靶点进行测试，了解这些药物可能对视力有什么影响是很重要的。此外，由于G11-mGluRs的表达并不局限于视网膜，因此更好地了解它们在视网膜中的功能将对我们理解正常和病理的脑功能具有更广泛的意义。在视网膜中，我们假设-Ill mGluRs组存在于双极细胞终末和无长突细胞中，在那里它们调节神经递质的释放。本项目的具体目的是：1)用免疫组织化学方法对兔视网膜G11 mGluRs进行定位；2)确定mGluR4、-R7和-R8刺激对星状突起无长突细胞和神经节细胞光反应的影响；3)确定G11 mGluRs在明视ERG振荡电位产生中的作用。

DESCRIPTION (provided by applicant): Glutamate is the major excitatory neurotransmitter in the vertebrate CNS. In the retina it is the neurotransmitter used along the feed-forward pathway from photoreceptors, to bipolar cells, to ganglion cells. Glutamatergic transmission is mediated by glutamate receptors, of which there are two broad classes: lonotropic glutamate receptors are ligand-gated ion channels. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors and their function is mediated by second messenger pathways. The objective of this project is to determine the distribution and function of group-Ill mGluRs in the inner plexiform layer of the retina. Group-Ill mGluRs are selectively activated by L-2-amino-4-phosphonobutyric acid (APB, also abbreviated L-AP4) and consist of mGluR4, -R6, -R7, and -R8. mGluR6 is present in ON bipolar cell dendrites and mediates the depolarizing response of these cells to light, generating the ON visual pathway. While the other group-Ill mGluRs are known to be widely expressed in the brain, indicating that they may be involved in a number of pathologies, their precise distribution and function in the retina is poorly characterized. Group-Ill mGluRs are currently tested as targets for therapeutic drugs, and it is important to know what effects on vision these drugs may have. Moreover, because the expression of group-Ill mGluRs is not restricted to the retina, a better understanding of their function in the retina will have broader significance for our understanding of normal and pathological brain function. In the retina, we hypothesize that group-Ill mGluRs are present in bipolar cell terminals and in amacrine cells where they regulate neurotransmitter release. The specific aims of this project are 1) to localize immunohistochemically group-Ill mGluRs in the rabbit retina; 2) to determine the effects of mGluR4, -R7 and -R8 stimulation on the light responses of starburst amacrine and ganglion cells; and 3) to determine the role of group-Ill mGluRs in the generation of photopic ERG oscillatory potentials.