DRUG DISCOVERY AND PERSONALIZED MEDICINE AROUND G-PROTEIN COUPLED RECEPTORS

许多G蛋白偶联受体（GPCR）以前被怀疑作为膜受体单体存在，在质膜上表达为同源/异源二聚体或多聚体。这一概念正在被广泛接受，并构成了GPCR细胞信号传导领域的一个新兴领域。本研究旨在表征模型GPCR异聚体在细胞，生物化学和药理学水平。我们以前已经确定，两个关键的神经调节受体，组胺3受体（H3）和多巴胺D1受体（D1），可以复合成异聚体。重新评估H3药理学，重点是异聚体，并根据我们目前对GPCR配体和下游信号传导（偏倚和变构）的复杂性的认识，可能会导致对神经控制理解的突破。研究H3的一个挑战是受体的多种亚型（剪接变体）的存在。这些同种型主要在受体的第三胞内环的大小上变化。在某些情况下，这些同种型似乎可以共存于同一细胞中。该研究的一个方面将是研究异构体之间的药理学差异，并了解这如何有助于H3的生理功能。对H3异聚体选择性超过同聚体的配体将作为探测异聚体功能的有力工具，并且该研究的另一方面将是在已知的H3配体中或通过筛选方法鉴定这样的选择性化合物。这项研究的最后一个方面，也是GPCR异聚体研究领域面临的一个关键问题，是了解异聚体的形成是如何被调控的。简单地说，在同一细胞膜中存在具有相互亲和力的不同GPCR可能足以驱动短暂或持久的关联，但有初步证据表明异聚体形成的时间调节。为了开始理解这一点，该项目将研究对异聚体形成重要的结构特征。

Many G-protein coupled receptors (GPCRs) previously suspected to exist as membrane receptor monomers are expressed on the plasma membrane as homo/heterodimers or multimers. This concept is becoming widely accepted and constitutes an emerging area in the field of GPCR cell signalling. This study seeks to characterize a model GPCR heteromer at the cellular, biochemical and pharmacological level. We have previously identified that two key neuromodulatory receptors, the Histamine 3 receptors (H3) and Dopamine D1 receptors (D1), can complex into heteromers. Reappraisal of H3 pharmacology with focus on heteromers and in light of our more current appreciation of the complexity of GPCR ligands and downstream signalling (bias and allosterism) may lead to breakthroughs in understanding of neural control. A challenge in studying H3 is the presence of multiple isoforms (splice variants) of the receptors. These isoforms vary predominantly in the size of the third intracellular loop of the receptor. In some cases it appears that these isoforms can co-exist in the same cell. An aspect of the study will be to investigate pharmacological differences between isoforms, and understand how this contributes to physiological function of H3. Ligands selective for H3 heteromers over homomers will serve as powerful tools to probe heteromer function, and a further aspect of the study will be to identify such selective compounds either amongst known H3 ligands or through screening approaches. The final aspect of the study, and a critical question facing the field of research into GPCR heteromers, is to understand how heteromer formation is regulated. Simply the presence of different GPCRs with mutual affinity in the same cell membrane may be sufficient to drive transient or long-lasting association, but there is preliminary evidence of temporal regulation of heteromer formation. To begin to understand this, the project will investigate structural features important to heteromer formation.