G-proteins and mechanisms of signal transduction in vision

描述（由申请人提供）：视网膜杆状光感受器细胞的光传导依赖于异源三聚体g蛋白转导蛋白介导的高产量信号放大的典型机制。一个光激活的视紫红质分子激活数百个转导蛋白分子，这些转导蛋白分子将视紫红质传入的视觉信号信息传递给第二信使系统的酶，cgmp -磷酸二酯酶。转导蛋白α亚基功能的所有方面，特别是其与视紫红质和视紫红质催化的核苷酸交换的主要相互作用，都需要转导蛋白α亚基复合物。二十多年前发现的转导蛋白- γ几乎完全通过体外实验进行研究。这种蛋白复合物在正常功能或视网膜疾病中真正的体内作用尚不清楚。我们开发了一种新的工具来研究g蛋白在视觉中的机制-一种缺乏棒特异性转导蛋白γ亚基的小鼠模型。为了表征这个模型系统，我们将提供给广泛的视觉研究界，我们建议测试光导，视网膜发育和蛋白质分布的主要方面。关键目标是确定是否有可能在没有转导蛋白- γ复合物的情况下激活视觉信号，这是目前体外研究尚未解决的问题。在未来，该模型还将有助于回答诸如光适应机制、视杆和视锥信号的差异、突触传递、视网膜退化等重要问题。g蛋白- γ复合物最近成为药物设计和治疗干预的新靶点。因此，该小鼠模型的功能特征将对了解人类眼病和潜在的新疗法非常有价值。

DESCRIPTION (provided by applicant): Phototransduction in retinal rod photoreceptor cells relies on the prototypical mechanism of high-yield signal amplification mediated by the heterotrimeric G-protein transducin. A single light activated rhodopsin molecule activates several hundred transducin molecules, which relay the information about incoming visual signal from rhodopsin to the enzyme of the second messenger system, cGMP-phosphodiesterase. All aspects of transducin alpha subunit functions, especially its primary interactions with rhodopsin and rhodopsin catalyzed nucleotide exchange, require the transducin beta-gamma subunit complex. Discovered more than two decades ago, transducin beta-gamma has been studied by in-vitro experiments almost exclusively. The true in-vivo role of this protein complex during normal functioning or its involvement in retina diseases remains unknown. We have developed a novel tool to study the mechanisms of G-proteins in vision - a mouse model lacking the rod specific transducin gamma subunit. To characterize this model system, which we will make available to the broad vision research community, we propose to test major aspects of phototransduction, retina development and protein distribution. The key goal is to determine whether activation of visual signaling is possible at all without transducin beta-gamma complex, a problem that is not resolved by current in-vitro studies. In the future this model will also help to answer such important questions, as mechanisms of light adaptation, differences between rod and cone signaling, synaptic transmission, retina degeneration and others. G-protein beta-gamma complexes have recently emerged as new targets of drug design and therapeutic intervention. Thus, the functional characterization of this mouse model will be very valuable for understanding eye disease and potential new therapies in humans. PUBLIC HEALTH RELEVANCE: This project focuses on the first characterization of the mouse model system in which a key retinal protein, transducin beta-gamma complex, has been deleted. This model is being developed for use by the vision research community to help understand underlying mechanisms of retinal diseases in humans and facilitate novel therapeutic strategies.