Cytoskeletal Control of Neuronal G Protein Signaling

描述(由申请人提供)： 神经元中的G蛋白信号最初被描述为一个线性序列 哪种激动剂与特定受体结合。这反过来又激活了一个 G蛋白的种类。然后，G蛋白继续激活或抑制 细胞内效应物，如腺酰环化酶、磷脂酶或各种离子 频道。在过去的几年里，G蛋白已经变得很明显 信令是一个复杂的过程。这种复杂性的一部分涉及直接 多种结合受体的分子对受体和G蛋白的调节 或磷酸化受体(阻滞素和受体激动酶)或增加GTP酶 G蛋白(RGS蛋白)的活性。一种更微妙的监管形式出现了 来自一系列改变细胞定位的蛋白质和脂类 G蛋白分子在膜上级联。其中一些是被动的 定位分子，但其他分子，如微管，提供动态 定位和激活G蛋白的相互作用。之间的接口 G蛋白和微管是双向的，因为某些Fty亚基稳定。 微管，而a亚基促进微管快速解聚。G 蛋白质在突触后密度高度集中，它是 假设它们的激活导致细胞骨架重排和 突触形状迅速改变。正是在这个框架下，提出了研究 在G的语境中探索结构与功能的关系 蛋白质信号。G蛋白和微管的几种成像工具 将在实验中使用，旨在发现这两个 系统。这些技术将与酶分析和 我们已成功地用光亲和标记法探索G的激活 蛋白质与荧光(正常和突变)G的功能活性 细胞和小鼠体内的蛋白质。G蛋白偶联受体及其下游 效应是当前神经药理学最喜欢的靶点。通过开发一种 更好地了解这些受体和G蛋白与 神经微环境--治疗慢性阻塞性肺疾病的新策略 大脑和思维很可能即将到来。

DESCRIPTION (provided by applicant): G protein signaling in neurons was originally described as a linear sequence in which agonist bound to a specific receptor. which in turn activated a single species of G protein. That G protein then went on to activate or inhibit intracellular effectors such as adenylyl cyclase, phospholipase or various ion channels. Over the past several years, it has become clear that G protein signaling is a complex process. Some of this complexity involves direct regulation of receptors and G proteins by a variety of molecules that bind to or phosphorylate receptors (arrestins and receptor kinases) or increase GTPase activity of G proteins (RGS proteins). A more subtle form of regulation appears to be from a series of proteins and lipids that alter the positioning of the molecules of the G protein cascade on the membrane. Some of these are passive positioning molecules, but others, such as microtubules, offer dynamic interactions that both position and activate G proteins. The interface between G proteins and microtubules is bidirectional, as certain fty subunits stabilize microtubules, while a subunits promote rapid microtubule depolymerization. G proteins are highly concentrated at the post-synaptic density and it is hypothesized that their activation leads to cytoskeletal rearrangement and rapid synaptic shape change. It is in this framework, that research is proposed to explore the relationship of structure and function within the context of G protein signaling. Several imaging tools for both G proteins and microtubules will be used in experiments designed to discover the interplay between these systems. These techniques will be combined with the enzyme assays and the photoaffinity labeling we have used successfully to probe the activation of G proteins and the functional activity of fluorescent (normal and mutant) G proteins in cells and in mice. G protein coupled receptors and their downstream effects are favorite targets of current neuropharmacology. By developing a better understanding of the relationship of those receptors and G proteins to the neuronal microenvironment, new therapeutic strategies for the diseases of brain and mind are likely to be forthcoming.