Regulation of retinal rod transducin

抽象的。 感觉信号依赖于由异三聚体G- 传递来自跨膜G-1的细胞外信号的蛋白质。 第二信使系统的酶的蛋白质偶联受体(GPCRs)。 这些级联反应中的功能缺陷会导致各种神经退行性疾病， 其中包括视网膜病变。此外，GPCRs也是最重要的 治疗性干预，占市场上近50%的药物。尽管 G蛋白的普遍分子机制研究进展 激活，G蛋白β-伽马亚单位复合体的生物学作用，及其 令人惊讶的是，从GPCR到G蛋白的信号传递过程中的确切作用仍然存在 默默无闻。由于存在多个β和伽马亚基亚型 细胞和冗余的G蛋白介导的许多基本途径 贝塔-伽马复合体生物学的问题在 生理条件。因此，这种蛋白质复合体功能的主要方面 仍未得到证实。这项建议建立在我们坚实的基础上，这些基础导致了 发现β-伽马复合体赋予视网膜视杆细胞感光能力 以放大视觉信号并确定这些感觉神经元的总体灵敏度 对光，以及调制信号失活和光适应。我们的研究 挑战当前将β-伽马复合体作为辅助物质的相当狭隘的观点 G蛋白的亚基，目的是确定这种蛋白复合体的生物学作用， 它在从GPCR到G蛋白的信号传递过程中的确切作用，特别是在 这一反应的关键激活步骤--G-蛋白α上的核苷酸交换 亚单位。通过使用生化、生理和分子生物物理的组合 方法，并通过使用几个独特的鼠标线，我们希望解开 β-伽马复合体在基本机制中的贡献 视网膜光感受器中的gpr信号和调控。就像贝塔-伽马复合体 作为药物设计和治疗干预的新靶点，这一提议将 从而更好地理解新疗法如何影响GPCR信号转导。

ABSTRACT. Sensory signaling relies on the prototypical pathway mediated by the heterotrimeric G- proteins, which relays the incoming extracellular signals from the transmembrane G- protein-coupled receptors (GPCRs) to the enzymes of the second messenger system. Functional defects in these cascades lead to a variety of neurodegenerative disorders, which include retinopathies. In addition, GPCRs are among the most important targets of therapeutic intervention, which account for nearly 50% of drugs on the market. Despite recent progress in understanding the universal molecular mechanism of G-protein activation, the biological role of the G-protein beta-gamma subunit complex, and its exact role during signal transfer from a GPCR to a G-protein remain surprisingly obscure. Due to the existence of multiple beta and gamma subunit isoforms in a typical cell and the redundancy of the G-protein-mediated pathways many fundamental questions of beta-gamma complex biology have been very difficult to address under the physiological conditions. Thus, major aspects of how this protein complex functions remain unproven. This proposal builds on our strong groundwork that led to the discovery that the beta-gamma complex confers the ability of retinal rod photoreceptors to amplify visual signals and determines the overall sensitivity of these sensory neurons to light, as well as modulates signal inactivation and light adaptation. Our studies challenge a rather narrow current view of the beta-gamma complex as an auxiliary subunit of the G-protein and aim at identifying the biological role of this protein complex, its exact role during signal transfer from a GPCR to a G-protein, especially during the key activating step of this reaction – nucleotide exchange on the G-protein alpha subunit. By using a combination of biochemical, physiological and molecular biophysical approaches, and by employing several unique mouse lines, we expect to unravel the contribution of the beta-gamma complex in the underlying mechanisms that are critical to GPCR signaling and regulation in retinal photoreceptors. As beta-gamma complex has emerged as a new target of drug design and therapeutic intervention, this proposal will lead to better understanding of how new therapies may affect GPCR signaling.