Molecular mechanisms of signal transduction in retina

描述（由申请人提供）：谷氨酸是脊椎动物CNS中的主要兴奋性神经递质。在视网膜中，它是沿着从光感受器到双极细胞再到神经节细胞的前馈通路使用的神经递质。谷氨酸能传递由谷氨酸受体介导，其中有两大类：离子型谷氨酸受体是配体门控离子通道。代谢型谷氨酸受体（mGluRs）是G蛋白偶联受体，其功能由第二信使途径介导。 该项目的目的是确定第III组mGluRs在视网膜的内部丛状层中的分布和功能。第III组mGluR被L-2-氨基-4-膦酰基丁酸（APB，也缩写为L-AP 4）选择性激活，并且由mGluR 4、-R6、-R7和-R8组成。mGluR 6存在于ON双极细胞树突中，并介导这些细胞对光的去极化反应，产生ON视觉通路。虽然已知其他第III组mGluR在脑中广泛表达，表明它们可能参与许多病理学，但它们在视网膜中的精确分布和功能的特征很差。第III组mGluRs目前作为治疗药物的靶点进行了测试，重要的是要知道这些药物可能对视力产生什么影响。此外，由于第III组mGluRs的表达不限于视网膜，因此更好地了解它们在视网膜中的功能将对我们了解正常和病理性脑功能具有更广泛的意义。在视网膜中，我们假设第三组mGluRs存在于双极细胞末端和无长突细胞中，在那里它们调节神经递质的释放。该项目的具体目的是1）化学定位兔视网膜中的第III组mGluR; 2）确定mGluR 4、-R7和-R8刺激对星爆无长突细胞和神经节细胞的光反应的影响;和3）确定第III组mGluR在产生明视ERG振荡电位中的作用。

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.