Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, China.
Int J Mol Sci. 2020 Sep 24;21(19):7036. doi: 10.3390/ijms21197036.
The melanocortin receptor 4 (MC4R) signaling system consists of MC4R, MC4R ligands [melanocyte-stimulating hormone (MSH), adrenocorticotropin (ACTH), agouti-related protein (AgRP)], and melanocortin-2 receptor accessory protein 2 (MRAP2), and it has been proposed to play important roles in feeding and growth in vertebrates. However, the expression and functionality of this system have not been fully characterized in teleosts. Here, we cloned tilapia , , (, ), and (, ) genes and characterized the interaction of tilapia MC4R with MRAP2b, AgRP, α-MSH, and ACTH in vitro. The results indicate the following. (1) Tilapia MC4R, MRAP2b, AgRPs, and POMCs share high amino acid identity with their mammalian counterparts. (2) Tilapia MRAP2b could interact with MC4R expressed in CHO cells, as demonstrated by Co-IP assay, and thus decrease MC4R constitutive activity and enhance its sensitivity to ACTH. (3) As in mammals, AgRP can function as an inverse agonist and antagonist of MC4R, either in the presence or absence of MRAP2b. These data, together with the co-expression of , , and in tilapia hypothalamus, suggest that as in mammals, ACTH/α-MSH, AgRP, and MRAP2 can interact with MC4R to control energy balance and thus play conserved roles in the feeding and growth of teleosts.
黑素皮质素受体 4 (MC4R) 信号系统由 MC4R、MC4R 配体（促黑素细胞激素 (MSH)、促肾上腺皮质激素 (ACTH)、刺鼠相关蛋白 (AgRP)）和黑素皮质素-2 受体辅助蛋白 2 (MRAP2) 组成，据推测，它在脊椎动物的摄食和生长中发挥重要作用。然而，该系统在硬骨鱼类中的表达和功能尚未完全阐明。在这里，我们克隆了罗非鱼 、 、 （ 、 ）和 （ 、 ）基因，并在体外研究了罗非鱼 MC4R 与 MRAP2b、AgRP、α-MSH 和 ACTH 的相互作用。结果表明：（1）罗非鱼 MC4R、MRAP2b、AgRPs 和 POMCs 与哺乳动物的对应物具有高度的氨基酸同一性。（2）MRAP2b 可以与 CHO 细胞中表达的 MC4R 相互作用，Co-IP 试验证实了这一点，从而降低 MC4R 的组成型活性并增强其对 ACTH 的敏感性。（3）与哺乳动物一样，AgRP 可以作为 MC4R 的反向激动剂和拮抗剂，无论是否存在 MRAP2b。这些数据，以及在罗非鱼下丘脑中共表达 、 、 、 ，表明与哺乳动物一样，ACTH/α-MSH、AgRP 和 MRAP2 可以与 MC4R 相互作用，以控制能量平衡，从而在硬骨鱼类的摄食和生长中发挥保守作用。
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