Receptor oligomerization in family B1 of G-protein-coupled receptors: focus on BRET investigations and the link between GPCR oligomerization and binding cooperativity.
Receptor oligomerization in family B1 of G-protein-coupled receptors: focus on BRET investigations and the link between GPCR oligomerization and binding cooperativity.
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DOI：
10.3389/fendo.2012.00062
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发表时间：
2012
影响因子：
5.2
通讯作者：
De Meyts P
中科院分区：
文献类型：
--
作者：
Roed SN;Orgaard A;Jorgensen R;De Meyts P
7个跨膜G蛋白偶联受体(7TM/GPCRs)超家族是最大的膜相关受体家族。GPCRs参与了许多人类疾病的病理生理学过程，估计占所有药物靶标的30%-40%。在过去的二十年里，利用生物发光共振能量转移(BRET)等方法对GPCR寡聚进行了广泛的研究，今天，GPCR超家族中的受体-受体相互作用是一个公认的现象。GPCR寡聚对配体结合、受体表达和信号转导等方面的影响的证据表明，这些受体相互作用具有重要的生理和药理学意义。与更大、更深入研究的GPCR亚家族A和C相比，B1亚家族很小，只有15个成员，包括促胰液素受体、胰高血糖素受体和甲状旁腺激素受体(PTHR1和PTHR2)。几个家族B1受体的失调与糖尿病、慢性炎症和骨质疏松症等疾病有关，这突显了这个GPCR亚家族的病理生理学重要性。尽管如此，对家族B1受体寡聚的研究，特别是其药理学意义的研究仍处于早期阶段。尽管GPCR寡聚是一种公认的现象，但还需要更多的研究来提供这些相互作用与B1GPCRs家族中的受体功能之间的直接联系。GPCR寡聚的功能效应的一个例子是促进变构作用，包括与GPCRs结合的配体的协同性。在这里，我们主要基于Bret的研究，对目前可用的关于B1GPCR同源和异构化的数据进行综述。此外，我们还讨论了齐聚作用对配体结合的功能影响以及齐聚作用与结合协作性之间的联系。
The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30–40% of all drug targets. During the last two decades, GPCR oligomerization has been extensively studied using methods like bioluminescence resonance energy transfer (BRET) and today, receptor–receptor interactions within the GPCR superfamily is a well-established phenomenon. Evidence of the impact of GPCR oligomerization on, e.g., ligand binding, receptor expression, and signal transduction indicates the physiological and pharmacological importance of these receptor interactions. In contrast to the larger and more thoroughly studied GPCR subfamilies A and C, the B1 subfamily is small and comprises only 15 members, including, e.g., the secretin receptor, the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality in family B1 GPCRs. One example of the functional effects of GPCR oligomerization is the facilitation of allosterism including cooperativity in ligand binding to GPCRs. Here, we review the currently available data on family B1 GPCR homo- and heteromerization, mainly based on BRET investigations. Furthermore, we cover the functional influence of oligomerization on ligand binding as well as the link between oligomerization and binding cooperativity.