Melatonin receptors: molecular pharmacology and signalling in the context of system bias
Melatonin receptors: molecular pharmacology and signalling in the context of system bias
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DOI：
10.1111/bph.13950
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发表时间：
2018-08-01
影响因子：
7.3
通讯作者：
Jockers, Ralf
中科院分区：
文献类型：
--
作者：
Cecon, Erika;Oishi, Atsuro;Jockers, Ralf
褪黑激素，N-乙酰基-5-甲氧基色胺，是一种进化上古老的分子，由脊椎动物的松果体产生，并且它以高亲和力结合褪黑激素受体，褪黑激素受体是GPCR家族的成员。在归因于褪黑激素的多种效应中，我们将在这里集中于那些依赖于两种哺乳动物MT 1和MT 2褪黑激素受体的激活的效应。本文综述了近年来褪黑素受体配体的合成研究进展，包括多靶点配体的合成和信号偏向配体的表征。我们讨论了褪黑激素受体激活的信号通路，似乎是高度细胞和组织依赖性，强调系统偏见的功能结果的影响。不同的蛋白质已被证明与褪黑激素受体相互作用，因此，我们推测，该系统的一部分偏见有其分子基础的受体相关蛋白，包括异源二聚化伙伴的表达差异。最后，通过遗传受体变体的表达，将讨论受体水平的偏倚，以显示修饰的受体功能如何对人类2型糖尿病等常见疾病的风险产生影响。
Melatonin, N-acetyl-5-methoxytryptamine, an evolutionally old molecule, is produced by the pineal gland in vertebrates, and it binds with high affinity to melatonin receptors, which are members of the GPCR family. Among the multiple effects attributed to melatonin, we will focus here on those that are dependent on the activation of the two mammalian MT1 and MT2 melatonin receptors. We briefly summarize the latest developments on synthetic melatonin receptor ligands, including multi-target-directed ligands, and the characterization of signalling-biased ligands. We discuss signalling pathways activated by melatonin receptors that appear to be highly cell- and tissue-dependent, emphasizing the impact of system bias on the functional outcome. Different proteins have been demonstrated to interact with melatonin receptors, and thus, we postulate that part of this system bias has its molecular basis in differences of the expression of receptor-associated proteins including heterodimerization partners. Finally, bias at the level of the receptor, by the expression of genetic receptor variants, will be discussed to show how a modified receptor function can have an effect on the risk for common diseases like type 2 diabetes in humans.