Molecular Evolution of Multiple Forms of Kisspeptins and GPR54 Receptors in Vertebrates
Molecular Evolution of Multiple Forms of Kisspeptins and GPR54 Receptors in Vertebrates
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DOI：
10.1210/en.2008-1679
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Tsutsui, Kazuyoshi
中科院分区：
文献类型：
--
作者：
Lee, Yeo Reum;Tsunekawa, Kenta;Tsutsui, Kazuyoshi
Kisspeptin及其受体GPR54在哺乳动物生殖和肿瘤转移中发挥重要作用。由于KiSS和GPR54基因已在有限数量的脊椎动物物种中被发现，主要是在哺乳动物中，因此对这些基因的进化史知之甚少。在目前的研究中，我们从多种脊椎动物物种中克隆了多种形式的kisspeptin和GPR54 cdna。我们发现鱼有两种形式的kisspeptin基因，KiSS-1和KiSS-2，而爪蟾有三种形式的kisspeptin基因，KiSS-1a， KiSS-1b和KiSS-2。发现非哺乳动物的KiSS-1基因与哺乳动物的KiSS-1基因同源，而KiSS-2基因是一种新的形式，编码非洲爪蟾大脑中c端修饰的十二肽。这项研究是首次在任何脊椎动物的大脑中鉴定出成熟形式的KiSS-2产物。同样地，鱼有两个受体，GPR54-1和GPR54-2，而爪蟾有三个受体，GPR54-1a， GPR54-1b和GPR54-2。序列鉴定和基因组同源性分析表明，非洲爪蟾GPR54-1a与人类GPR54同源，而非洲爪蟾GPR54-1b与鱼类GPR54-1同源。kisspeptin和GPR54s都在爪蟾的大脑中大量表达，特别是在下丘脑中，这表明这些配体-受体对具有神经内分泌和神经调节作用。合成的KiSS-1和KiSS-2肽以不同的效价激活CV-1细胞中表达的GPR54s，表明配体选择性存在差异。这些数据为脊椎动物kisspeptin-GPR54系统的分子进化提供了新的思路。（内分泌学150:2837-2846,2009）
Kisspeptin and its receptor GPR54 play important roles in mammalian reproduction and cancer metastasis. Because the KiSS and GPR54 genes have been identified in a limited number of vertebrate species, mainly in mammals, the evolutionary history of these genes is poorly understood. In the present study, we have cloned multiple forms of kisspeptin and GPR54 cDNAs from a variety of vertebrate species. We found that fish have two forms of kisspeptin genes, KiSS-1 and KiSS-2, whereas Xenopus possesses three forms of kisspeptin genes, KiSS-1a, KiSS-1b, and KiSS-2. The nonmammalian KiSS-1 gene was found to be the ortholog of the mammalian KiSS-1 gene, whereas the KiSS-2 gene is a novel form, encoding a C-terminally amidated dodecapeptide in the Xenopus brain. This study is the first to identify a mature form of KiSS-2 product in the brain of any vertebrate. Likewise, fish possess two receptors, GPR54-1 and GPR54-2, whereas Xenopus carry three receptors, GPR54-1a, GPR54-1b, and GPR54-2. Sequence identity and genome synteny analyses indicate that Xenopus GPR54-1a is a human GPR54 ortholog, whereas Xenopus GPR54-1b is a fish GPR54-1 ortholog. Both kisspeptins and GPR54s were abundantly expressed in the Xenopus brain, notably in the hypothalamus, suggesting that these ligand-receptor pairs have neuroendocrine and neuromodulatory roles. Synthetic KiSS-1 and KiSS-2 peptides activated GPR54s expressed in CV-1 cells with different potencies, indicating differential ligand selectivity. These data shed new light on the molecular evolution of the kisspeptin-GPR54 system in vertebrates. (Endocrinology 150: 2837-2846, 2009)