Synaptic Mechanisms in Retina

描述(申请人提供)：我们计划探索两个新的代谢性G蛋白偶联受体(GPCRs)：一个对甜味配体敏感，另一个被甘氨酸激活。GPCRs代表了参与神经元功能的不同蛋白质家族。GPCRs在视网膜中的重要性是显而易见的，因为这对受体负责光传导(视紫红质)和整个视觉通路中On反应(MGluR6)的形成。此外，两种主要的视网膜神经递质，GABA和谷氨酸，激活整个神经视网膜的GPCRs。我们在大鼠视网膜中发现了两种味觉受体蛋白，它们与舌头中的相同。与舌头不同，视网膜中缺少关键的第三个蛋白质亚单位。令人惊讶的是，存在的两个亚基足以检测甜味剂，它们检测到一些在老鼠舌头中没有检测到的甜味剂，而且它们对甜味剂比舌头更敏感。我们建议检验这一假设，即视网膜神经元拥有一种新的系统，对细胞外葡萄糖做出反应，并且该系统可以影响突触传递。味觉感受器可能对正常的视网膜功能和糖尿病很重要。我们最近还发现了视网膜中存在代谢性甘氨酸受体的证据。这是甘氨酸激活亲离子受体和代谢性受体的第一个证据。由于甘氨酸是视网膜的三大神经递质系统之一，我们将测试甘氨酸调节双极细胞和无长突细胞输出并与GABA激活的代谢性受体相反的假设。 与公共健康相关：这项拨款提案将解决视网膜中新型“甜味感受器”的功能。我们假设这些新发现的受体可以影响正常视网膜的功能，以及在糖尿病情况下这种情况可能会如何改变。我们还将探索一种控制视网膜抑制的新甘氨酸受体。

DESCRIPTION (provided by applicant): We propose to explore two novel metabotropic G-protein coupled receptors (GPCRs): one that is sensitive to sweet taste ligands and another that is activated by glycine. GPCRs represent a diverse family of proteins involved in neuronal function. The importance of GPCRs in retina is obvious because a pair of these receptors are responsible for phototransduction (rhodopsin) and for the formation of ON responses (mGluR6) throughout the visual pathway. Furthermore, two of the primary retinal neurotransmitters, GABA and glutamate, activate GPCRs throughout the neural retina. We found two taste receptor proteins in rat retina that are identical to those in the tongue. Unlike the tongue, a key third protein subunit is missing in retina. Surprisingly, the two subunits that are present are sufficient to detect sweet tastants, they detect some sweet tastants not detected in rat tongue, and they are more sensitive to sweet tastants than the tongue. We propose to test the hypothesis that retinal neurons possess a novel system that responds to extracellular glucose and that this system can influence synaptic transmission. Taste receptors may be important in normal retinal function and in diabetes. We have also recently found evidence for a metabotropic glycine receptor in retina. This is the first evidence that glycine activates metabotropic as well as ionotropic receptors. Since glycine is one of the three major neurotransmitter systems in retina, we will test the hypotheses that glycine regulates bipolar and amacrine cell outputs and acts in opposition to GABA activated metabotropic receptors. PUBLIC HEALTH RELEVANCE: This grant proposal will address the function of novel "sweet taste receptors" in retina. We hypothesize that these newly discovered receptors can influence how the normal retina functions and how that might change in diabetic conditions. We will also explore a new glycine receptor that controls inhibition in the retina.