Effects of antidepressants on the conformation of phospholipid headgroups studied by solid-state NMR
Effects of antidepressants on the conformation of phospholipid headgroups studied by solid-state NMR
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DOI：
10.1002/mrc.1327
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发表时间：
2004-02-01
影响因子：
2
通讯作者：
Ramamoorthy, A
中科院分区：
文献类型：
--
作者：
Santos, JS;Lee, DK;Ramamoorthy, A
研究三环类抗抑郁药(TCA)对磷脂双层结构和动力学的影响，为深入了解TCA诱导细胞内脂质蓄积(称为类脂沉积)的机制提供依据。具体地说，我们询问脂质-TCA相互作用是否是TCA或脂质特异性的，以及这种物理相互作用是否会导致脂肪沉积。用P-31和N-14固体核磁共振技术研究了磷脂酰胆碱-磷脂酰甘油(PC-PG)混合磷脂多层囊泡和机械取向双层膜中的相互作用。在TCA存在下双层结构的变化被观察到依赖于TCA的有效电荷和空间约束。结果进一步表明，地塞帕明和丙咪嗪在膜表面引起了明显的变化，特别是在磷脂的头基有序性、构象和动力学方面。地塞帕明增加了磷脂酰胆碱头基上胆碱位置的无序性，而磷酸盐区域的构象和动力学基本保持不变。丙咪嗪的掺入改变了脂头基团的构象和动力学。我们的结果表明，TCA诱导的双层结构变化与这些化合物诱导脂肪沉积的能力之间的相关性并不是直接的，因为丙咪嗪比地昔帕明引起更显著的双层构象和动力学变化。使用N-14作为探头有助于得出上述结论。版权所有(C)2004 John Wiley Sons，Ltd.
The effect of tricyclic antidepressants (TCA) on phospholipid bilayer structure and dynamics was studied to provide insight into the mechanism of TCA-induced intracellular accumulation of lipids (known as lipidosis). Specifically we asked if the lipid-TCA interaction was TCA or lipid specific and if such physical interactions could contribute to lipidosis. These interactions were probed in multilamellar vesicles and mechanically oriented bilayers of mixed phosphatidylcholine-phosphatidylglyceroI (PC-PG) phospholipids using P-31 and N-14 solid-state NMR techniques. Changes in bilayer architecture in the presence of TCAs were observed to be dependent on the TCA's effective charge and steric constraints. The results further show that desipramine and imipramine evoke distinguishable changes on the membrane surface, particularly on the headgroup order, conformation and dynamics of phospholipids. Desipramine increases the disorder of the choline site at the phosphatidylcholine headgroup while leaving the conformation and dynamics of the phosphate region largely unchanged. Incorporation of imipramine changes both lipid headgroup conformation and dynamics. Our results suggest that a correlation between TCA-induced changes in bilayer architecture and the ability of these compounds to induce lipidosis is, however, not straightforward as imipramine was shown to induce more dramatic changes in bilayer conformation and dynamics than desipramine. The use of N-14 as a probe was instrumental in arriving at the presented conclusions. Copyright (C) 2004 John Wiley Sons, Ltd.