Stereospecific requirement of cholesterol in the function of the serotonin1A receptor.
Stereospecific requirement of cholesterol in the function of the serotonin1A receptor.
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DOI：
10.1016/j.bbamem.2013.08.015
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Chattopadhyay A
中科院分区：
文献类型：
--
作者：
Jafurulla M;Rao BD;Sreedevi S;Ruysschaert JM;Covey DF;Chattopadhyay A
降钙素1A受体是G蛋白偶联受体（GPCR）家族的重要成员。它参与各种认知和行为功能的产生和调节，并作为药物靶标。我们实验室以前的工作已经确定了胆固醇1A受体功能对膜胆固醇的敏感性。利用两性离子去污剂CHAPS溶解海马体降钙素1A受体伴随着胆固醇的损失，并导致特异性配体结合减少。胆固醇补充到溶解的膜恢复特异性配体与受体的结合。我们利用这一策略的甾醇补充溶解的膜，探索立体特异性严格的胆固醇受体功能。我们使用胆固醇的两种立体异构体，对映胆固醇（胆固醇的对映异构体）和表胆固醇（胆固醇的非对映异构体）用于此目的。重要的是，我们在这里表明，虽然内毒素胆固醇可以取代胆固醇支持受体功能，表胆固醇不能。这些结果意味着，膜胆固醇的要求，为胆固醇1A受体功能是非对映体特异性，但不是对映体特异性。我们的研究结果扩展和帮助定义特异性的膜胆固醇与胆固醇1A受体的相互作用，并代表了第一份报告，利用ent-胆固醇检查GPCR-胆固醇相互作用的立体特异性。
The serotonin1A receptor is an important member of the G protein-coupled receptor (GPCR) family. It is involved in the generation and modulation of a variety of cognitive and behavioral functions, and serves as a drug target. Previous work from our laboratory has established the sensitivity of the function of the serotonin1A receptor to membrane cholesterol. Solubilization of the hippocampal serotonin1A receptor utilizing the zwitterionic detergent CHAPS is accompanied by loss of cholesterol and results in reduction in specific ligand binding. Replenishment of cholesterol to solubilized membranes restores specific ligand binding to the receptor. We utilized this strategy of sterol replenishment of solubilized membranes to explore the stereospecific stringency of cholesterol for receptor function. We used two stereoisomers of cholesterol, ent-cholesterol (enantiomer of cholesterol) and epi-cholesterol (a diastereomer of cholesterol) for this purpose. Importantly, we show here that while ent-cholesterol could replace cholesterol in supporting receptor function, epi-cholesterol could not. These results imply that the requirement of membrane cholesterol for the serotonin1A receptor function is diastereospecific, yet not enantiospecific. Our results extend and help define specificity of the interaction of membrane cholesterol with the serotonin1A receptor, and represent the first report utilizing ent-cholesterol to examine stereospecificity of GPCR-cholesterol interaction.
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影响因子：
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