Biological and Pharmacological Roles of HCA Receptors
Biological and Pharmacological Roles of HCA Receptors
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DOI：
10.1016/b978-0-12-385952-5.00005-1
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发表时间：
2011-01-01
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影响因子：
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通讯作者：
Offermanns, Stefan
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文献类型：
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作者：
Blad, Clara C.;Ahmed, Kashan;Offermanns, Stefan
羟基羧酸(HCA)受体Hca(1)、Hca(2)和Hca(3)分别被称为GPR81、Gpr109a和GPR109B，或烟酸受体家族。它们形成了一组具有高度序列同源性的G蛋白偶联受体。最近，能量代谢的中间产物，所有的HCA，被报道为这些受体的内源性配体。HCA受体主要表达在脂肪细胞上，通过偶联G(I)型蛋白来抑制脂解作用。Hca(1)被乳酸激活，Hca(2)被酮体3-羟基丁酸酯激活，Hca(3)被羟化的β-氧化中间体，特别是3-羟基辛酸激活。Hca(2)和Hca(3)都是负反馈环路的一部分，在饥饿条件下控制脂肪的释放，而Hca(1)在胰岛素的降脂(保存脂肪)作用中发挥作用。Hca(2)首次被发现是抗血脂药物烟酸(或烟酸)的分子靶标。自那以后，许多合成激动剂被设计用于HCA(2)和HCA(3)，但尽管进行了许多临床研究，但到目前为止，针对HCA的新的、改进的靶向药物的开发尚未成功。最近，研究表明，烟酸的主要副作用，皮肤潮红，是通过Hca(2)受体在角质形成细胞和皮肤的朗格汉斯细胞上介导的。在本章中，我们综述了HCA受体研究领域的最新进展，重点介绍了HCA受体的(病理)生理学、受体药理学、主要配体类别以及HCA配体的治疗潜力。
The hydroxy-carboxylic acid (HCA) receptors HCA(1), HCA(2), and HCA(3) were previously known as GPR81, GPR109A, and GPR109B, respectively, or as the nicotinic acid receptor family. They form a cluster of G protein-coupled receptors with high sequence homology. Recently, intermediates of energy metabolism, all HCAs, have been reported as endogenous ligands for each of these receptors. The HCA receptors are predominantly expressed on adipocytes and mediate the inhibition of lipolysis by coupling to G(i)-type proteins. HCA(1) is activated by lactate, HCA(2) by the ketone body 3-hydroxy-butyrate, and HCA(3) by hydroxylated beta-oxidation intermediates, especially 3-hydroxy-octanoic acid. Both HCA(2) and HCA(3) are part of a negative feedback loop which keeps the release of fat stores in check under starvation conditions, whereas HCA(1) plays a role in the antilipolytic (fat-conserving) effect of insulin.HCA(2) was first discovered as the molecular target of the antidyslipidemic drug nicotinic acid (or niacin). Many synthetic agonists have since been designed for HCA(2) and HCA(3), but the development of a new, improved HCA-targeted drug has not been successful so far, despite a number of clinical studies. Recently, it has been shown that the major side effect of nicotinic acid, skin flushing, is mediated by HCA(2) receptors on keratinocytes, as well as on Langerhans cells in the skin. In this chapter, we summarize the latest developments in the field of HCA receptor research, with emphasis on (patho) physiology, receptor pharmacology, major ligand classes, and the therapeutic potential of HCA ligands.