Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Biomolecules. 2022 Feb 2;12(2):244. doi: 10.3390/biom12020244.
The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new human (h) splice variants, (465 bp open reading frame) and (381 bp open reading frame). Human MRAP2s are different in C-termini. We investigated the effects of five isoforms of MRAPs, hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c, on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a and hMRAP2c increased and hMRAP1b decreased the cell surface expression. hMRAP1a increased affinity to ACTH. Four MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, and hMRAP2c) decreased the maximal responses in response to α-MSH and ACTH. For hMC4R, hMRAP1a, hMRAP2a, and hMRAP2c increased the cell surface expression of hMC4R. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R trafficking, binding, and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s.
神经黑素皮质素受体 (MCRs)，黑素皮质素-3 和 -4 受体 (MC3R 和 MC4R)，在调节能量平衡方面发挥着重要的非冗余作用。神经 MCRs 和黑素皮质素-2 受体辅助蛋白 (MRAPs，MRAP1 和 MRAP2) 的相互作用被认为在 MC3R 和 MC4R 信号转导中发挥关键作用。在本研究中，我们鉴定了两种新的人类 (h) 剪接变体， (465 bp 开放阅读框) 和 (381 bp 开放阅读框)。人类 MRAP2s 在 C 末端不同。我们研究了五种 MRAPs 同工型，hMRAP1a、hMRAP1b、hMRAP2a、hMRAP2b 和 hMRAP2c，对 MC3R 和 MC4R 药理学的影响。在 hMC3R 上，hMRAP1a 和 hMRAP2c 增加了细胞表面表达，而 hMRAP1b 降低了细胞表面表达。hMRAP1a 增加了 ACTH 的亲和力。四种 MRAPs (hMRAP1a、hMRAP1b、hMRAP2a 和 hMRAP2c) 降低了对 α-MSH 和 ACTH 的最大反应。对于 hMC4R，hMRAP1a、hMRAP2a 和 hMRAP2c 增加了 hMC4R 的细胞表面表达。人类 MRAP1b 显著增加了 ACTH 的亲和力，而 MRAP2a 降低了 ACTH 的亲和力。hMRAP1a 增加了 ACTH 的效力。MRAPs 还影响 hMC4R 的基础活性，hMRAP1s 增加，hMRAP2s 减少基础活性。总之，新鉴定的剪接变体 hMRAP2b 和 hMRAP2c 可以调节 MC3R 和 MC4R 药理学。两种 MRAP1s 和三种 MRAP2s 对 MC3R 和 MC4R 的转运、结合和信号转导有不同的影响。这些发现使我们更好地理解了 MRAP1s 和 MRAP2s 对神经 MCRs 的调节。
