G 蛋白偶联受体同型二聚体和异型二聚体：作为药物开发靶点是否优于 G 蛋白偶联受体单体？
GPCR homomers and heteromers: a better choice as targets for drug development than GPCR monomers?
机构信息
Departament de Bioquímica i Biologia Molecular, CIBERNED (Centro de Investigación en Red de Enfermedades Neurodegenerativas) and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain.
出版信息
Pharmacol Ther. 2009 Nov;124(2):248-57. doi: 10.1016/j.pharmthera.2009.07.005. Epub 2009 Aug 5.
Abstract
G protein-coupled receptors (GPCR) are targeted by many therapeutic drugs marketed to fight against a variety of diseases. Selection of novel lead compounds are based on pharmacological parameters obtained assuming that GPCR are monomers. However, many GPCR are expressed as dimers/oligomers. Therefore, drug development may consider GPCR as homo- and hetero-oligomers. A two-state dimer receptor model is now available to understand GPCR operation and to interpret data obtained from drugs interacting with dimers, and even from mixtures of monomers and dimers. Heteromers are distinct entities and therefore a given drug is expected to have different affinities and different efficacies depending on the heteromer. All these concepts would lead to broaden the therapeutic potential of drugs targeting GPCRs, including receptor heteromer-selective drugs with a lower incidence of side effects, or to identify novel pharmacological profiles using cell models expressing receptor heteromers.
摘要
G 蛋白偶联受体（GPCR）是许多治疗药物的靶点，这些药物被用于对抗各种疾病。新型先导化合物的选择是基于药理学参数获得的，这些参数假设 GPCR 是单体。然而，许多 GPCR 以二聚体/寡聚体的形式表达。因此，药物开发可以将 GPCR 视为同型和异型寡聚体。现在有一个二态二聚体受体模型可用于理解 GPCR 的运作，并解释与二聚体相互作用的药物获得的数据，甚至是来自单体和二聚体混合物的数据。异源二聚体是不同的实体，因此，取决于异源二聚体，给定的药物预计会具有不同的亲和力和不同的效力。所有这些概念将扩大靶向 GPCR 的药物的治疗潜力，包括具有较低副作用发生率的受体异源二聚体选择性药物，或者使用表达受体异源二聚体的细胞模型来识别新的药理学特征。
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1
Useful pharmacological parameters for G-protein-coupled receptor homodimers obtained from competition experiments. Agonist-antagonist binding modulation.从竞争实验中获得的G蛋白偶联受体同源二聚体的有用药理学参数。激动剂-拮抗剂结合调节。
Biochem Pharmacol. 2009 Dec 15;78(12):1456-63. doi: 10.1016/j.bcp.2009.07.012. Epub 2009 Jul 28.
2
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Br J Pharmacol. 2009 Sep;158(1):23-31. doi: 10.1111/j.1476-5381.2009.00181.x. Epub 2009 May 5.
3
Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors.多巴胺D1受体与组胺H3受体异聚化后信号转导的显著变化。
Br J Pharmacol. 2009 May;157(1):64-75. doi: 10.1111/j.1476-5381.2009.00152.x.
4
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5
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Nat Chem Biol. 2009 Mar;5(3):131-4. doi: 10.1038/nchembio0309-131.
6
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7
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