Characterization of Compartmentalized GPCR Signaling in Neurons

超过三分之一的G蛋白偶联受体（GPCRs）在大脑中表达，它们在大脑中调节 突触可塑性，记忆和行为，也有助于病理生理学 神经精神障碍因此，更好地了解GPCR如何 一些神经和 在神经元中运行的原理是 对神经科学至关重要，并将使基于机制的发现更具选择性， 有效治疗记忆障碍和精神疾病。在这份提案中，我们建立在我们的变革性基础上， 发现内体区室上的受体活化是独特的细胞反应的基础。我们提出 探索神经元内体受体信号传导的分子后果，并研究如何 神经元区分不同的局部激活位点。我们集中在原型β2-肾上腺素受体 （β2-AR），一种公认的神经元功能介质，以检验以下假设： 存在于内体的信号复合物不同于质膜，导致独特的神经元信号复合物。 β2-AR激活后的结果。我们将采用跨学科的方法在人类iPSC衍生的神经元 1）描述区室化β2-AR信号对转录重编程的影响，2） 阐明质膜和内体β2-AR在基因表达的翻译调节中的作用， 和3）确定内体如何诱导空间偏向的GPCR反应。成功完成这些 研究将阐明空间GPCR调控是如何建立的，以及它如何塑造关键的神经元输出， 这条路。

More than a third of all G protein-coupled receptors (GPCRs) are expressed in the brain, where they modulate synaptic plasticity, memory and behavior, and also contribute to the pathophysiology of neuropsychiatric disorders. Therefore, improved understanding of how GPCRs several neurological and operate in neurons is fundamentally important to neuroscience, and will enable mechanism-based discovery of more selective and efficient therapies for memory disorders and mental illness. In this proposal, we build on our transformative finding that receptor activation on endosomal compartments underlies unique cellular responses. We propose to explore the molecular consequences of endosomal receptor signaling in neurons, and to investigate how neurons discriminate between distinct sites of local activation. We focus on the prototypical β2-adrenoceptor (β2-AR), a recognized mediator of neuronal function, to test the hypothesis that the molecular composition of signaling complexes present at endosomes is distinct from the plasma membrane resulting in unique neuronal outcomes upon β2-AR activation. We will employ an interdisciplinary approach in human iPSC-derived neurons to 1) delineate the consequences of compartmentalized β2-AR signaling on transcriptional reprogramming, 2) elucidate the role of plasma membrane- and endosomal β2-ARs in translational regulation of gene expression, and 3) determine how the endosome induces spatially biased GPCR responses. Successful completion of these studies will illuminate how spatial GPCR regulation is established, and how it shapes critical neuronal outputs of this pathway.