G protein-coupled receptors (GPCRs) are transmembrane receptors that mediate a large number of cellular responses. The organization of GPCRs into dimers and higher-order oligomers is known to allow a larger repertoire of downstream signaling events. In this context, a crosstalk between the adenosine and dopamine receptors has been reported, indicating the presence of heterodimers that are functionally relevant. In this paper, we explored the effect of membrane cholesterol on the adenosine2A (A2A) and dopamine D3 (D3) receptors using coarse-grain molecular dynamics simulations. We analyzed cholesterol interaction sites on the A2A receptor and were able to reproduce the sites indicated by crystallography and previous atomistic simulations. We predict novel cholesterol interaction sites on the D3 receptor that could be important in the reported cholesterol sensitivity in receptor function. Further, we analyzed the formation of heterodimers between the two receptors. Our results suggest that membrane cholesterol modulates the relative population of several co-existing heterodimer conformations. Both direct receptor-cholesterol interaction and indirect membrane effects contribute toward the modulation of heterodimer conformations. These results constitute one of the first examples of modulation of GPCR hetero-dimerization by membrane cholesterol, and could prove to be useful in designing better therapeutic strategies.

中文翻译：

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胆固醇介导的作用在GPCR异二聚体中的作用。

G蛋白偶联受体（GPCR）是介导大量细胞反应的跨膜受体。已知将GPCR组织为二聚体和更高阶的低聚物可允许更大范围的下游信号转导事件。在这种情况下，已经报道了腺苷和多巴胺受体之间的串扰，表明存在功能相关的异二聚体。在本文中，我们使用粗粒分子动力学模拟研究了膜胆固醇对腺苷2A（A2A）和多巴胺D3（D3）受体的影响。我们分析了A2A受体上的胆固醇相互作用位点，并能够再现晶体学和以前的原子模拟所指示的位点。我们预测D3受体上新的胆固醇相互作用位点可能对所报告的受体功能中的胆固醇敏感性很重要。此外，我们分析了两种受体之间异源二聚体的形成。我们的结果表明，膜胆固醇可调节几种同时存在的异二聚体构象的相对种群。受体与胆固醇的直接相互作用和膜的间接作用都有助于异二聚体构象的调节。这些结果构成了通过膜胆固醇调节GPCR异源二聚化的第一个实例之一，并且可能被证明可用于设计更好的治疗策略。我们的结果表明，膜胆固醇可调节几种同时存在的异二聚体构象的相对种群。受体与胆固醇的直接相互作用和膜的间接作用都有助于异二聚体构象的调节。这些结果构成了通过膜胆固醇调节GPCR异源二聚化的第一个实例之一，并且可能被证明可用于设计更好的治疗策略。我们的结果表明，膜胆固醇可调节几种同时存在的异二聚体构象的相对种群。受体与胆固醇的直接相互作用和膜的间接作用都有助于异二聚体构象的调节。这些结果构成了通过膜胆固醇调节GPCR异源二聚化的第一个实例，并且可能被证明可用于设计更好的治疗策略。