Ojeda-Naharros Irene, Das Tirthasree, Castro Ralph A, Bazan J Fernando, Vaisse Christian, Nachury Maxence V
Department of Ophthalmology, University of California San Francisco, California, United States of America.
Cardiovascular Research Institute, University of California San Francisco, California, United States of America.
PLoS Biol. 2025 Feb 3;23(2):e3003025. doi: 10.1371/journal.pbio.3003025. eCollection 2025 Feb.
The G protein-coupled receptor (GPCR) melanocortin receptor 4 (MC4R) is an essential regulator of body weight homeostasis. MC4R is unusual among GPCRs in that its activity is regulated by 2 opposing physiological ligands, the agonist ⍺-MSH and the antagonist/inverse agonist AgRP. Paradoxically, while MC4R localizes and functions at the cilium of hypothalamic neurons, the ciliary levels of MC4R are very low under unrestricted feeding conditions. Here, we find that the constitutive activity of MC4R is responsible for the continuous depletion of MC4R from cilia and that inhibition of MC4R's activity via AgRP leads to a robust accumulation of MC4R in cilia. Ciliary targeting of MC4R is mediated by its partner MRAP2 and the constitutive exit of MC4R from cilia relies on the sensor of activation β-arrestin, on ubiquitination, and on the BBSome ciliary trafficking complex. Thus, while MC4R exits cilia via conventional mechanisms, it only accumulates in cilia when its activity is suppressed by AgRP.
G蛋白偶联受体（GPCR）黑皮质素受体4（MC4R）是体重稳态的重要调节因子。MC4R在GPCR中较为特殊，其活性受两种相反的生理性配体调节，即激动剂α-促黑素（α-MSH）和拮抗剂/反向激动剂刺鼠肽蛋白（AgRP）。矛盾的是，尽管MC4R定位于下丘脑神经元的纤毛并在其中发挥作用，但在无限制进食条件下，MC4R在纤毛中的水平非常低。在此，我们发现MC4R的组成性活性导致其从纤毛中持续耗竭，而通过AgRP抑制MC4R的活性会导致MC4R在纤毛中大量积累。MC4R向纤毛的靶向定位由其伴侣黑色素皮质素受体辅助蛋白2（MRAP2）介导，并且MC4R从纤毛的组成性排出依赖于激活传感器β-抑制蛋白、泛素化以及BBSome纤毛运输复合体。因此，虽然MC4R通过传统机制离开纤毛，但只有当其活性被AgRP抑制时，它才会在纤毛中积累。
