Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors.
Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors.
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DOI：
10.1038/srep19839
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发表时间：
2016-01-22
影响因子：
4.6
通讯作者：
Selent J
中科院分区：
文献类型：
--
作者：
Guixà-González R;Javanainen M;Gómez-Soler M;Cordobilla B;Domingo JC;Sanz F;Pastor M;Ciruela F;Martinez-Seara H;Selent J
二十二碳六烯酸（DHA）是一种必需的ω-3多不饱和脂肪酸（ω-3 PUFA），其膜水平在常见的神经精神疾病中降低。DHA调节关键的细胞膜特性，如流动性，从而影响跨膜蛋白如G蛋白偶联受体（GPCR）的行为。这些受体与主要的神经精神疾病特别相关，最近已被证明可形成二聚体或更高级的寡聚体，有证据表明DHA水平通过调节寡聚化作用影响GPCR功能。在这项研究中，我们评估了膜DHA含量对一类与脑部疾病特别相关的蛋白质复合物形成的影响：腺苷A2 A和多巴胺D2受体寡聚体。使用广泛的多尺度计算机建模，我们发现DHA与A2 A和D2受体相互作用的明显倾向，这导致受体寡聚化的速率增加。在活细胞上进行的生物发光共振能量转移（BRET）实验表明，DHA对A2 A和D2受体寡聚化的影响纯粹是动力学的。这项工作首次揭示了膜ω-3 PUFAs在GPCR寡聚动力学中发挥关键作用，这可能对精神分裂症或帕金森病等神经精神疾病具有重要意义。
Membrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω-3 PUFA), are decreased in common neuropsychiatric disorders. DHA modulates key cell membrane properties like fluidity, thereby affecting the behaviour of transmembrane proteins like G protein-coupled receptors (GPCRs). These receptors, which have special relevance for major neuropsychiatric disorders have recently been shown to form dimers or higher order oligomers, and evidence suggests that DHA levels affect GPCR function by modulating oligomerisation. In this study, we assessed the effect of membrane DHA content on the formation of a class of protein complexes with particular relevance for brain disease: adenosine A2A and dopamine D2 receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A2A and D2 receptors, which leads to an increased rate of receptor oligomerisation. Bioluminescence resonance energy transfer (BRET) experiments performed on living cells suggest that this DHA effect on the oligomerisation of A2A and D2 receptors is purely kinetic. This work reveals for the first time that membrane ω-3 PUFAs play a key role in GPCR oligomerisation kinetics, which may have important implications for neuropsychiatric conditions like schizophrenia or Parkinson’s disease.