Mountjoy K G, Willard D H, Wilkison W O
Research Centre for Developmental Medicine and Biology, Department of Paediatrics, University of Auckland, New Zealand.
Endocrinology. 1999 May;140(5):2167-72. doi: 10.1210/endo.140.5.6748.
Desacetyl-alpha-MSH is more abundant than alpha-MSH in the brain, the fetus, human blood, and amniotic fluid, but there is little information on its ability to interact with melanocortin receptors. The aim of this study is to compare and contrast the ability of desacetyl-alpha-MSH and alpha-MSH to couple melanocortin receptors stably expressed in HEK293 cells, to the protein kinase A (PKA) signaling pathway. Desacetyl-alpha-MSH activated mouse MC1, MC3, MC4 and MC5 receptors with EC50s = 0.13, 0.96, 0.53, and 0.84 nM, and alpha-MSH activated these receptors with EC50s = 0.17, 0.88, 1.05, and 1.34 nM, respectively. Mouse agouti protein competitively antagonized alpha-MSH and desacetyl-alpha-MSH coupling to the MC1-R similarly. In contrast, mouse agouti protein antagonized desacetyl-alpha-MSH much more effectively and potently than alpha-MSH coupling the MC4-R to the PKA signaling pathway. Furthermore, mouse agouti protein (10 nM) significantly reduced (1.4-fold) the maximum response of mMC4-R to desacetyl-alpha-MSH and 100 nM mouse agouti significantly increased (4.8-fold) the EC50. Minimal antagonism of alpha-MSH coupling mMC4-R to the PKA signaling pathway was observed with 10 nM mouse agouti, whereas both 50 and 100 nM mouse agouti appeared to reduce the maximum reponse (1.1- and 1.3-fold, respectively) and increase the EC50 (2.5- and 3.4-fold respectively). Mouse agouti protein did not significantly antagonize either alpha-MSH or desacetyl-alpha-MSH coupling mouse MC3 and MC5 receptors. Understanding the similarities and differences in activation of melanocortin receptors by desacetyl-alpha-MSH and alpha-MSH will contribute to delineating the functional roles for these endogenous melanocortin peptides.
去乙酰化α-促黑素（Desacetyl-alpha-MSH）在大脑、胎儿、人体血液和羊水中比α-促黑素更为丰富，但关于其与黑皮质素受体相互作用能力的信息却很少。本研究的目的是比较和对比去乙酰化α-促黑素和α-促黑素与稳定表达于HEK293细胞中的黑皮质素受体偶联至蛋白激酶A（PKA）信号通路的能力。去乙酰化α-促黑素激活小鼠MC1、MC3、MC4和MC5受体，其半数有效浓度（EC50）分别为0.13、0.96、0.53和0.84纳摩尔，而α-促黑素激活这些受体的EC50分别为0.17、0.88、1.05和1.34纳摩尔。小鼠刺鼠蛋白（agouti蛋白）同样竞争性拮抗α-促黑素和去乙酰化α-促黑素与MC1-R的偶联。相比之下，小鼠刺鼠蛋白拮抗去乙酰化α-促黑素比其拮抗α-促黑素偶联MC4-R至PKA信号通路更为有效和强力。此外，小鼠刺鼠蛋白（10纳摩尔）显著降低（1.4倍）mMC4-R对去乙酰化α-促黑素的最大反应，而100纳摩尔小鼠刺鼠蛋白显著增加（4.8倍）其EC50。观察到10纳摩尔小鼠刺鼠蛋白对α-促黑素偶联mMC4-R至PKA信号通路的拮抗作用极小，而50和100纳摩尔小鼠刺鼠蛋白似乎分别降低最大反应（分别为1.1倍和1.3倍）并增加EC50（分别为2.5倍和3.4倍）。小鼠刺鼠蛋白对α-促黑素或去乙酰化α-促黑素偶联小鼠MC3和MC5受体均无显著拮抗作用。了解去乙酰化α-促黑素和α-促黑素激活黑皮质素受体的异同将有助于阐明这些内源性黑皮质素肽的功能作用。
