Structure and function of Cannabinoid Receptor Heterodimers

G蛋白偶联受体(G蛋白偶联受体)通过配基结合后的构象变化发挥作用，从而导致蛋白质之间的动态相互作用。多个A型GPCR在物理上结合在异构体复合体中，对配体结合的信号响应取决于复合体中的GPCRs。鉴于不同细胞类型中GPCRs的不同偶联，不同脑区对内源性配体和神经递质的反应比之前想象的要复杂得多。人们越来越有兴趣了解含有大麻素受体的异构体与其他GPCRs包括其他大麻素受体、多巴胺受体、腺苷受体和阿片受体的复合体的独特性质。异构体复合体对内源性配体(如内源性大麻素)的信号传递取决于受体的相对浓度、参与异构体复合体的受体的比例以及内源性配体的局部浓度。这项工作是一项长期研究计划的一部分，目的是了解异构体GPCRs如何控制基本的动态平衡过程，包括外周和大脑中神经传递、神经发生、脑血管功能和免疫反应的调节。该研究计划的结果将提供有关ECS功能的新信息，目前ECS已被公认为哺乳动物大脑的主要神经和免疫调节剂。具体地说，我们将有助于理解大脑和外周之间的神经血管边界在正常发育、衰老和炎症期间的复杂调节。

G protein-coupled receptors (GPCR) function via conformational change in response to ligand binding resulting in dynamic protein-protein interactions. Multiple type A GPCR physically associate in heteromeric complexes and the signalling response to ligand binding is dependent on the GPCRs in the complex. Given the differential coupling of GPCRs in different cell types, the response to endogenous ligands and neurotransmitters in different brain regions is more complex than imagined previously. There is a growing interest in understanding the unique properties of heteromers containing cannabinoid receptors in complex with other GPCRs including other cannabinoid receptors, dopamine receptors, adenosine receptors and opioid receptors. The signalling of heteromeric complexes in response to endogenous ligands such as endocannabinoids depends on the relative concentration of receptors, proportion of receptors involved in heteromeric complexes and the local concentration of endogenous ligands.  The work proposed is part of a long-term research program to understand how heteromeric GPCRs control basic homeostatic processes including modulation of neurotransmission, neurogenesis, cerebral vascular function and immune responses in the periphery and in the brain. The results of this research program will provide novel information on the function of the ECS, which is now recognized as a major neuro- and immunomodulator for the mammalian brain. Specifically, we will contribute the understanding of the complex regulation of the neurovascular boundary between the brain and periphery during normal development, aging, and during periods of inflammation.