Membrane cholesterol effect on the 5-HT2A receptor: Insights into the lipid-induced modulation of an antipsychotic drug target
Membrane cholesterol effect on the 5-HT2A receptor: Insights into the lipid-induced modulation of an antipsychotic drug target
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DOI：
10.1002/bab.1608
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发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Selent, Jana
中科院分区：
文献类型：
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作者：
Manuel Ramirez-Anguita, Juan;Rodriguez-Espigares, Ismael;Selent, Jana
血清素5-羟色胺2A（5-HT 2A）受体是与CNS病症的治疗相关的G蛋白偶联受体（GPCR）。在这方面，脑中的神经元膜组成在受体功能的调节中起着至关重要的作用。由于胆固醇是神经细胞膜的重要组成部分，我们研究了它对5-HT 2A受体动力学的影响，通过全原子分子动力学模拟。我们发现，胆固醇在膜中的存在下增加受体的构象变异性在大多数受体片段。重要的是，详细的结构分析表明，构象变化沿着氢键网络的不稳定，不仅在受体内，而且在受体和脂质之间。除了增加构象变异性，我们还发现受体片段的可变性降低。我们的分析表明，这种增加的稳定性是与受体表面紧密结合的胆固醇分子的稳定作用的结果。我们的发现有助于更好地理解膜诱导的受体动力学的改变，并指出胆固醇诱导的稳定和不稳定的影响GPCR的构象变异。
The serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor is a G-protein-coupled receptor (GPCR) relevant for the treatment of CNS disorders. In this regard, neuronal membrane composition in the brain plays a crucial role in the modulation of the receptor functioning. Since cholesterol is an essential component of neuronal membranes, we have studied its effect on the 5-HT2A receptor dynamics through all-atom MD simulations. We find that the presence of cholesterol in the membrane increases receptor conformational variability in most receptor segments. Importantly, detailed structural analysis indicates that conformational variability goes along with the destabilization of hydrogen bonding networks not only within the receptor but also between receptor and lipids. In addition to increased conformational variability, we also find receptor segments with reduced variability. Our analysis suggests that this increased stabilization is the result of stabilizing effects of tightly bound cholesterol molecules to the receptor surface. Our finding contributes to a better understanding of membrane-induced alterations of receptor dynamics and points to cholesterol-induced stabilizing and destabilizing effects on the conformational variability of GPCRs.