Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany (A.A., S.E.); and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (S.E.).
Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany (A.A., S.E.); and DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (S.E.)
Pharmacol Rev. 2014 Jul;66(3):598-637. doi: 10.1124/pr.113.008219.
The human genome encodes nine different adrenoceptor genes. These are grouped into three families, namely, the α1-, α2-, and β-adrenoceptors, with three family members each. Adrenoceptors are expressed by most cell types of the human body and are primary targets of the catecholamines epinephrine and norepinephrine that are released from the sympathetic nervous system during its activation. Upon catecholamine binding, adrenoceptors change conformation, couple to and activate G proteins, and thereby initiate various intracellular signaling cascades. As the primary receivers and transducers of sympathetic activation, adrenoceptors have a central role in human physiology and disease and are important targets for widely used drugs. All nine adrenoceptor subtypes display substantial genetic variation, both in their coding sequence as well as in adjacent regions. Despite the fact that some of the adrenoceptor variants range among the most frequently studied genetic variants assessed in pharmacogenetics to date, their functional relevance remains ill defined in many cases. A substantial fraction of the associations reported from early candidate gene approaches have not subsequently been confirmed in different cohorts or in genome-wide association studies, which have increasingly been conducted in recent years. This review aims to provide a comprehensive overview of all adrenoceptor variants that have reproducibly been detected in the larger genome sequencing efforts. We evaluate these variants with respect to the modulation of receptor function and expression and discuss their role in physiology and disease.
人类基因组编码了九种不同的肾上腺素能受体基因。这些基因分为三组，即 α1、α2 和 β肾上腺素能受体，每组有三个成员。肾上腺素能受体存在于人体大多数细胞类型中，是儿茶酚胺肾上腺素和去甲肾上腺素从交感神经系统在其激活时释放出来的主要靶点。儿茶酚胺结合后，肾上腺素能受体改变构象，与 G 蛋白偶联并激活，从而启动各种细胞内信号级联反应。作为交感神经激活的主要受体和转导器，肾上腺素能受体在人体生理学和疾病中具有核心作用，是广泛使用的药物的重要靶点。所有九种肾上腺素受体亚型在其编码序列以及相邻区域都存在大量遗传变异。尽管一些肾上腺素能受体变体是迄今为止在药物遗传学中评估的最常研究的遗传变体之一，但在许多情况下，它们的功能相关性仍然不明确。早期候选基因方法报告的大量关联在不同队列或全基因组关联研究中并未得到后续证实，近年来此类研究越来越多。这篇综述旨在全面概述在较大规模基因组测序工作中反复检测到的所有肾上腺素能受体变体。我们评估了这些变体对受体功能和表达的调节，并讨论了它们在生理学和疾病中的作用。
