Shanghai Key Laboratory of Signaling and Disease Research, Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China.
J Cell Physiol. 2021 Sep;236(9):6344-6361. doi: 10.1002/jcp.30306. Epub 2021 Jan 31.
Melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R), two neural G protein-coupled receptors are known to be functionally critical for energy balance in vertebrates. As allosteric regulators of melanocortin receptors, melanocortin accessory proteins (MRAPs) are also involved in energy homeostasis. The interaction of MRAPs and melanocortin signaling was previously shown in mammals and zebrafish, but nothing had been reported in amphibians. As the basal class of tetrapods, amphibians occupy a phylogenetic transition between teleosts and terrestrial animals. Here we examined the evolutionary conservation of MC3R, MC4R, and MRAPs between diploid Xenopus tropicalis (xt-) and other chordates and investigated the pharmacological regulatory properties of MRAPs on the neural MC3R and MC4R signaling. Our results showed that xtMRAP and xtMRAP2 both exerted robust potentiation effect on agonist (α-MSH and adrenocorticotropin [ACTH]) induced activation and modulated the basal activity and cell surface translocation of xtMC3R and xtMC4R. In addition, the presence of two accessory proteins could convert xtMC3R and xtMC4R into ACTH-preferred receptors. These findings suggest that the presence of MRAPs exhibits fine control over the pharmacological activities of the neuronal MC3R and MC4R signaling in the Xenopus tropicalis, which is physiologically relevant with the complicated transition of feeding behaviors during their life history.
黑皮质素-3 受体 (MC3R) 和黑皮质素-4 受体 (MC4R) 是两种神经 G 蛋白偶联受体，已知在脊椎动物的能量平衡中具有功能关键性。作为黑皮质素受体的别构调节剂，黑皮质素辅助蛋白 (MRAPs) 也参与能量稳态。MRAPs 和黑皮质素信号之间的相互作用以前在哺乳动物和斑马鱼中得到证实，但在两栖动物中尚未有报道。作为四足动物的基干类群，两栖动物在硬骨鱼和陆地动物之间的进化过渡中占有一席之地。在这里，我们检查了二倍体非洲爪蟾 (xt-) 和其他脊索动物之间 MC3R、MC4R 和 MRAPs 的进化保守性，并研究了 MRAPs 对神经 MC3R 和 MC4R 信号的药理学调节特性。我们的结果表明，xtMRAP 和 xtMRAP2 都对激动剂 (α-MSH 和促肾上腺皮质激素 [ACTH]) 诱导的激活产生了强大的增效作用，并调节了 xtMC3R 和 xtMC4R 的基础活性和细胞表面易位。此外，两种辅助蛋白的存在可以将 xtMC3R 和 xtMC4R 转化为 ACTH 偏好受体。这些发现表明，MRAPs 的存在对非洲爪蟾中神经元 MC3R 和 MC4R 信号的药理学活性表现出精细的控制，这与它们生命史中复杂的摄食行为转变在生理上相关。
