Paila Yamuna Devi, Chattopadhyay Amitabha
Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, 500 007, India.
Subcell Biochem. 2010;51:439-66. doi: 10.1007/978-90-481-8622-8_16.
Cholesterol is an essential component of higher eukaryotic membranes and plays a crucial role in membrane organization, dynamics and function. The G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas. Membrane cholesterol has been reported to have a modulatory role in the function of a number of GPCRs. Two possible mechanisms have been previously suggested by which membrane cholesterol could influence the structure and function of GPCRs (i) through a direct/specific interaction with GPCRs, or (ii) through an indirect way by altering membrane physical properties in which the receptor is embedded, or due to a combination of both. Recently reported crystal structures of GPCRs have shown structural evidence of cholesterol binding sites. Against this backdrop, we recently proposed a novel mechanism by which membrane cholesterol could affect structure and function of GPCRs. According to our hypothesis, cholesterol binding sites in GPCRs could represent 'nonannular' binding sites. Interestingly, previous work from our laboratory has demonstrated that membrane cholesterol is required for the function of the serotonin(1A) receptor (a representative GPCR), which could be due to specific interaction of the receptor with cholesterol. Based on these results, we envisage that there could be specific/nonannular cholesterol binding site(s) in the serotonin(1A) receptor. We have analyzed putative cholesterol binding sites from protein databases in the serotonin(1A) receptor. Our analysis shows that cholesterol binding sites are inherent characteristic features of serotonin(1A) receptors and are conserved through natural evolution. Progress in deciphering molecular details of the GPCR-cholesterol interaction in the membrane would lead to better insight into our overall understanding of GPCR function in health and disease, thereby enhancing our ability to design better therapeutic strategies to combat diseases related to malfunctioning of GPCRs.
胆固醇是高等真核生物细胞膜的重要组成部分，在膜的组织、动态变化及功能方面发挥着关键作用。G蛋白偶联受体（GPCRs）是参与跨膜信号转导的最大一类分子，是所有临床领域新型候选药物研发的主要靶点。据报道，膜胆固醇对多种GPCRs的功能具有调节作用。此前曾提出两种可能的机制，通过它们膜胆固醇可影响GPCRs的结构和功能：（i）通过与GPCRs直接/特异性相互作用；或（ii）通过间接方式，即改变受体所嵌入的膜的物理性质，或由于两者的结合。最近报道的GPCRs晶体结构已显示出胆固醇结合位点的结构证据。在此背景下，我们最近提出了一种膜胆固醇可能影响GPCRs结构和功能的新机制。根据我们的假设，GPCRs中的胆固醇结合位点可能代表“非环状”结合位点。有趣的是，我们实验室之前的工作表明，血清素（1A）受体（一种代表性的GPCR）的功能需要膜胆固醇，这可能是由于该受体与胆固醇的特异性相互作用。基于这些结果，我们设想血清素（1A）受体中可能存在特异性/非环状胆固醇结合位点。我们已经分析了血清素（1A）受体蛋白质数据库中的假定胆固醇结合位点。我们的分析表明，胆固醇结合位点是血清素（1A）受体固有的特征，并且在自然进化过程中是保守的。膜中GPCR-胆固醇相互作用分子细节解析方面的进展将使我们更好地洞察GPCRs在健康和疾病中的整体功能，从而增强我们设计更好治疗策略以对抗与GPCRs功能失调相关疾病的能力。
