Wellendorph Petrine, Johansen Lars Dan, Bräuner-Osborne Hans
UNIK centre for life-style diseases, Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mol Pharmacol. 2009 Sep;76(3):453-65. doi: 10.1124/mol.109.055244. Epub 2009 Jun 1.
A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium-sensing receptor, the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3, which are sensing L-alpha-amino acids, the carbohydrate-sensing T1R2/T1R3 receptor, the proteolytic degradation product sensor GPR93 (also termed GPR92), and the free fatty acid (FFA) sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. The involvement of the individual receptors in sensing of food intake has been validated to different degrees because of limited availability of specific pharmacological tools and/or receptor knockout mice. However, as a group, the receptors represent potential drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance.
在过去几年中，已克隆并鉴定了许多具有高度多配体选择性的七跨膜（7TM）受体。值得注意的是，这些受体中的许多都能被氨基酸、蛋白水解降解产物、碳水化合物或游离脂肪酸广泛激活，并在味觉组织、胃肠道、内分泌腺、脂肪组织和/或肾脏中表达。因此，这些受体有可能作为食物摄入的传感器，例如调节肠道中肠促胰岛素激素的释放、胰腺中胰岛素/胰高血糖素的释放以及脂肪组织中瘦素的释放。这些受体在配体识别上的多配体选择性倾向与大多数受体与一种生理激动剂的典型特异性相互作用形成对比，这对经典的“锁钥”概念提出了挑战。我们在此综述钙敏感受体、G蛋白偶联受体家族C第6组成员A（GPRC6A）以及味觉受体T1R1/T1R3对营养物质感知的分子机制，它们可感知L-α-氨基酸；碳水化合物感知受体T1R2/T1R3；蛋白水解降解产物传感器GPR93（也称为GPR92）；以及游离脂肪酸（FFA）感知受体FFA1、FFA2、FFA3、GPR84和GPR120。由于特异性药理学工具和/或受体敲除小鼠的可用性有限，各个受体在食物摄入感知中的参与程度已在不同程度上得到验证。然而，作为一个整体，这些受体代表了潜在的药物靶点，例如通过强效激动剂或正变构调节剂模拟食物摄入来治疗II型糖尿病。因此，有机营养物质的多配体选择性受体的配体-受体相互作用仍然是一个具有新兴功能重要性的有趣课题。
