Role of Receptor Dimerization in G Protein Activation

描述(由申请人提供)：本计划的长期目标 是为了确定G蛋白偶联受体的分子机制 将信号转化为细胞。这一信息将对 了解细胞信号、发育和疾病的基本方面 机械装置。对这个重要的受体超家族如何发挥作用的见解 配体激活的开关将有助于药物设计并对医学产生重大影响 目前超过一半的处方药针对G蛋白偶联 感受器。作用于这些受体的新疗法的潜力是巨大的； 据估计，人类基因组中有3%编码G蛋白偶联受体。 尽管它们具有广泛的重要性，但我们不知道受体是如何 实际上起到了配体激活开关的作用。最近的证据表明 G蛋白偶联受体，如肾上腺素能和多巴胺受体， 形成同源二聚体；8和K-阿片受体已被证明形成 具有新药理的杂二聚体。对于受体是否存在，我们知之甚少 通过特定的二聚体界面或更大的寡聚体结构相互作用， 受体二聚化/寡聚化的生理学意义 是其他G蛋白偶联受体的一般机制。要解决这些问题 基本问题，这项提议使用了各种技术，包括 基因研究、荧光能量转移、生物化学交联以及 计算机建模。这些研究将在人类补体上进行 因子5(C5a)受体，一种介导中性粒细胞的趋化受体 趋化性。这种受体在酵母中表达时功能良好，使 C5a受体可能的高通量结构/功能研究。在……里面 在哺乳动物细胞中的平行研究，从遗传基因获得的信息 研究将被用来提出关于受体激活的具体问题 二聚化/寡聚化在受体中的作用及其机制 功能。这些研究应该会增加我们对受体的了解 G蛋白信号的激活机制。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to identify the molecular mechanisms by which G protein-coupled receptors transduce signals into cells. This information will be important for understanding fundamental aspects of cell signaling, development, and disease mechanisms. Insights into how this important receptor superfamily works as ligand-activated switches will aid in drug design and greatly impact medicine more than half of currently prescribed pharmaceuticals target G protein-coupled receptors. The potential for new therapies acting on these receptors is great; an estimated 3 percent of the human genome encodes G protein-coupled receptors. Despite their widespread importance, we do not understand how the receptors actually function as ligand-activated switches. Recent evidence demonstrates that G protein-coupled receptors, such as adrenergic and dopamine receptors, form homodimers; the 8 and K-opiate receptors have been shown to form heterodimers with novel pharmacology. Little is known about if the receptors interact via specific dimer interfaces or larger oligomeric structures, the physiologic significance of receptor dimerization/oligomerization, and if this is a general mechanism for other G protein-coupled receptors. To address these fundamental questions, this proposal employs a variety of techniques including genetic studies, fluorescence energy transfer, biochemical crosslinking, and computer modeling. These studies will be performed on the human complement factor 5 (C5a) receptor, a chemoattractant receptor that mediates neutrophil chemotaxis. This receptor functions well when expressed in yeast, making possible high-throughput structure/function studies on the C5a receptor. In parallel studies in mammalian cells, the information gained from the genetic studies wifl be used to ask specific questions regarding receptor activation mechanisms and if dimerization / oligomerization plays a role in receptor function. These studies should add to our understanding of the receptor activation mechanisms for G protein signaling.