CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India.
CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Adv Exp Med Biol. 2019;1115:21-52. doi: 10.1007/978-3-030-04278-3_2.
G protein-coupled receptors (GPCRs) are the largest and a diverse family of proteins involved in signal transduction across biological membranes. GPCRs mediate a wide range of physiological processes and have emerged as major targets for the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, regulation of their organization, dynamics, and function by membrane lipids, in particular membrane cholesterol, has emerged as an exciting area of research. Cholesterol sensitivity of GPCRs could be due to direct interaction of cholesterol with the receptor (specific effect). Alternately, GPCR function could be influenced by the effect of cholesterol on membrane physical properties (general effect). In this review, we critically analyze the specific and general mechanisms of the modulation of GPCR function by membrane cholesterol, taking examples from representative GPCRs. While evidence for both the proposed mechanisms exists, there appears to be no clear-cut distinction between these two mechanisms, and a combination of these mechanisms cannot be ruled out in many cases. We conclude that classifying the mechanism underlying cholesterol sensitivity of GPCR function merely into these two mutually exclusive classes could be somewhat arbitrary. A more holistic approach could be suitable for analyzing GPCR-cholesterol interaction.
G 蛋白偶联受体（GPCRs）是最大和最多样化的蛋白质家族之一，参与跨生物膜的信号转导。GPCRs 介导广泛的生理过程，已成为所有临床领域新型药物候选物开发的主要靶点。由于 GPCRs 是整合膜蛋白，因此膜脂质（特别是膜胆固醇）对其组织、动力学和功能的调节已成为一个令人兴奋的研究领域。GPCR 对胆固醇的敏感性可能是由于胆固醇与受体的直接相互作用（特异性效应）。或者，GPCR 的功能可能会受到胆固醇对膜物理性质的影响（一般效应）。在这篇综述中，我们以有代表性的 GPCR 为例，批判性地分析了膜胆固醇对 GPCR 功能的调节的具体和一般机制。虽然这两种机制的证据都存在，但这两种机制之间似乎没有明显的区别，在许多情况下，不能排除这两种机制的结合。我们得出的结论是，将 GPCR 功能的胆固醇敏感性的机制简单地分为这两种相互排斥的类别可能有些任意。更全面的方法可能更适合分析 GPCR-胆固醇相互作用。
