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Exploring oligomeric state of the serotonin1A receptor utilizing photobleaching image correlation spectroscopy: implications for receptor function
Faraday Discussions ( IF 3.3 ) Pub Date : 2017-10-06 , DOI: 10.1039/c7fd00192d Hirak Chakraborty 1, 2, 3, 4, 5 , Md. Jafurulla 1, 2, 3 , Andrew H. A. Clayton 6, 7, 8, 9, 10 , Amitabha Chattopadhyay 1, 2, 3
Faraday Discussions ( IF 3.3 ) Pub Date : 2017-10-06 , DOI: 10.1039/c7fd00192d Hirak Chakraborty 1, 2, 3, 4, 5 , Md. Jafurulla 1, 2, 3 , Andrew H. A. Clayton 6, 7, 8, 9, 10 , Amitabha Chattopadhyay 1, 2, 3
Affiliation
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The oligomerization of G protein-coupled receptors (GPCRs) represents an important process in GPCR function and drug discovery. We have addressed cholesterol-dependent oligomerization state of the serotonin1A receptor, a representative GPCR and an important drug target, utilizing photobleaching image correlation spectroscopy (pbICS). pbICS allows determination of oligomeric state of membrane receptors since change in cluster density upon photobleaching is dependent on the oligomeric state. Our results show that oligomeric state of the serotonin1A receptor is modulated by cell membrane cholesterol and a trimeric population of the receptor prevails in control (normal) cholesterol conditions. Interestingly, upon lowering membrane cholesterol, the predominant oligomeric population of the receptor changes to dimers. This is associated with an increase in specific ligand binding activity of the receptor, thereby implying a crucial role of receptor dimers in ligand binding activity. Upon cholesterol replenishment, the distribution of receptor oligomers is further changed such that the trimers become the major population, with a concomitant restoration of ligand binding activity to the control level. These results demonstrate the utility of pbICS in monitoring oligomeric states of membrane receptors in general, and the cholesterol-dependent oligomeric state of the serotonin1A receptor in particular. We envision that functional correlates of oligomeric states of GPCRs could provide better understanding of GPCR function in health and disease, and help design better therapeutic strategies.
中文翻译：
利用光漂白图像相关光谱研究5-羟色胺1A受体的低聚状态：对受体功能的影响
G蛋白偶联受体（GPCR）的寡聚代表了GPCR功能和药物发现中的重要过程。我们已经利用光漂白图像相关光谱法（pbICS）解决了血清素1A受体，代表性GPCR和重要药物靶点的胆固醇依赖性寡聚化状态。pbICS可以确定膜受体的低聚状态，因为光漂白后簇密度的变化取决于低聚状态。我们的结果表明，血清素1A处于低聚状态受体受细胞膜胆固醇的调节，在控制（正常）胆固醇条件下，受体的三聚体群占主导地位。有趣的是，在降低膜胆固醇时，受体的主要寡聚群体变为二聚体。这与受体的特异性配体结合活性的增加有关，从而暗示受体二聚体在配体结合活性中的关键作用。胆固醇补充后，受体低聚物的分布进一步改变，使得三聚体成为主要种群，伴随的是配体结合活性恢复至对照水平。这些结果证明了pbICS在监测一般膜受体的低聚状态以及血清素的胆固醇依赖性低聚状态方面的实用性特别是1A受体。我们设想，GPCR的寡聚状态的功能相关性可以更好地了解GPCR在健康和疾病中的功能，并有助于设计更好的治疗策略。
更新日期：2018-04-17
中文翻译：
利用光漂白图像相关光谱研究5-羟色胺1A受体的低聚状态：对受体功能的影响
G蛋白偶联受体（GPCR）的寡聚代表了GPCR功能和药物发现中的重要过程。我们已经利用光漂白图像相关光谱法（pbICS）解决了血清素1A受体，代表性GPCR和重要药物靶点的胆固醇依赖性寡聚化状态。pbICS可以确定膜受体的低聚状态，因为光漂白后簇密度的变化取决于低聚状态。我们的结果表明，血清素1A处于低聚状态受体受细胞膜胆固醇的调节，在控制（正常）胆固醇条件下，受体的三聚体群占主导地位。有趣的是，在降低膜胆固醇时，受体的主要寡聚群体变为二聚体。这与受体的特异性配体结合活性的增加有关，从而暗示受体二聚体在配体结合活性中的关键作用。胆固醇补充后，受体低聚物的分布进一步改变，使得三聚体成为主要种群，伴随的是配体结合活性恢复至对照水平。这些结果证明了pbICS在监测一般膜受体的低聚状态以及血清素的胆固醇依赖性低聚状态方面的实用性特别是1A受体。我们设想，GPCR的寡聚状态的功能相关性可以更好地了解GPCR在健康和疾病中的功能，并有助于设计更好的治疗策略。
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