AMPA Receptor Cycling in the Retina

AMPA 受体在视网膜中循环

• 批准号: 7796249
• 负责人: SCOTT NAWY
• 金额: $ 1.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796249
• 关键词: AMPA Receptors; Binding; Binding Proteins; Biochemical; Biological Assay; Cells; Data; Development; Exhibits; Glutamate Receptor; Glutamates; Hippocampus (Brain); Light; Link; Measures; Mediating; Membrane; Molecular; Mus; Neurons; Pattern; Physiological; Play; Process; Proteins; Regulation; Research Personnel; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Transduction; Site; Stimulus; Surface; Synapses; Synaptic Membranes; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Time; ganglion cell; human RIPK1 protein; insight; neurotransmission; neurotransmitter release; novel; postsynaptic; programs; receptor; research study; retinal neuron; synaptic function; trafficking; transmission process

DESCRIPTION (provided by applicant): The rapid cycling of AMPA receptors (AMPARs) into and out of the membrane maintains neurotransmission at a number of CNS synapses. The cycling of AMPARs in the hippocampus and cortex is dynamically regulated by changes in levels of basal synaptic transmission and has been proposed to play a role in certain forms of synaptic plasticity. It remains unclear, however, whether the cycling of AMPARs also occurs at synapses not believed to exhibit postsynaptic forms of activity dependent plasticity. Additionally the question remains as to whether there are differences in the regulation of receptor trafficking at synapses that are subject to very different patterns of synaptic activation. For example, while many CNS synapses function primarily through intermittent, activity driven neurotransmitter release, synapses in the retina are subject to tonic glutamate release and stimulus dependent cessation of synaptic transmission. We are investigating the trafficking of AMPARs in retinal neurons and its regulation by activity. Our preliminary data demonstrates that, GluR2-containing AMPARs, can be rapidly cycled at the extrasynaptic membrane in the retina. However, contrary to in hippocampal synapses, activity in the retina stabilizes AMPARs in a non-cycling mode. This reversible process is modulated by physiological light stimuli. Experiments in this proposal, will seek to test the hypothesis, that normal light/dark cycles drive changes in the cycling of GluR2-containihg AMPARs thereby impacting functional signaling in the retina. Experiments in Aim 1 will establish the physiological conditions that mediate changes in the cycling of AMPARs in the retina. In Aim 2 we will seek to determine the molecular mechanisms by which activity links to changes in the cycling of AMPARs. Finally, in Aim 3 we will characterize the physiological significance of altered AMPAR cycling on the function of synaptic transmission in the retina. Results from these experiments will greatly enhance our understanding of the function and regulation .of signaling in the retina potentially identifying the existence a previously unknown form activity dependent of retinal plasticity. This should provide valuable insight into possible therapeutic treatments relevant to diseases of retinal development and degeneration.

描述（由申请人提供）：将AMPA受体（AMPARS）迅速循环进入膜，以许多CNS突触保持神经传递。海马和皮层中AMPAR的循环受基础突触传递水平的变化动态调节，并已提议在某些形式的突触可塑性中发挥作用。然而，尚不清楚AMPAR的循环是否也发生在不认为表现出突触后活性依赖性可塑性的突触处。此外，问题仍然是关于突触的受体运输调节是否存在差异，这些受体运输受到突触激活的截然不同的模式。例如，尽管许多CNS突触主要通过间歇性的，活动驱动的神经递质释放功能，但视网膜中的突触却受到强直性谷氨酸释放和依赖于突触传播的刺激的限制。我们正在研究视网膜神经元中AMPAR的贩运及其通过活动调节。我们的初步数据表明，含GLUR2的AMPAR可以迅速循环在视网膜中的外鼻膜外膜。但是，与海马突触相反，视网膜中的活性在非周期模式下稳定了AMPAR。这种可逆过程是通过生理光刺激来调节的。该提案中的实验将试图检验假设，即正常的光/暗周期驱动Glur2-Containihg Ampars循环的变化，从而影响视网膜中的功能信号。 AIM 1中的实验将建立介导视网膜中AMPAR循环变化的生理条件。在AIM 2中，我们将寻求确定活性与AMPAR循环变化相关的分子机制。最后，在AIM 3中，我们将表征AMPAR循环改变视网膜突触传播功能的生理意义。这些实验的结果将极大地增强我们对视网膜功能和调节的理解。这应该为与视网膜发育和变性疾病有关的可能的治疗治疗提供宝贵的见解。