Centre for Discovery Brain Sciences, School of Biomedical Sciences, University of Edinburgh, Edinburgh, UK.
Endocrinology. 2022 Jul 1;163(7). doi: 10.1210/endocr/bqac083.
The 5 known melanocortin receptors (MCs) have established physiological roles. With the exception of MC2, these receptors can behave unpredictably, and since they are more widely expressed than their established roles would suggest, it is likely that they have other poorly characterized functions. The aim of this review is to discuss some of the less well-explored aspects of the 4 enigmatic members of this receptor family (MC1,3-5) and describe how these are multifaceted G protein-coupled receptors (GPCRs). These receptors appear to be promiscuous in that they bind several endogenous agonists (products of the proopiomelanocortin [POMC] gene) and antagonists but with inconsistent relative affinities and effects. We propose that this is a result of posttranslational modifications that determine receptor localization within nanodomains. Within each nanodomain there will be a variety of proteins, including ion channels, modifying proteins, and other GPCRs, that can interact with the MCs to alter the availability of receptor at the cell surface as well as the intracellular signaling resulting from receptor activation. Different combinations of interacting proteins and MCs may therefore give rise to the complex and inconsistent functional profiles reported for the MCs. For further progress in understanding this family, improved characterization of tissue-specific functions is required. Current evidence for interactions of these receptors with a range of partners, resulting in modulation of cell signaling, suggests that each should be studied within the full context of their interacting partners. The role of physiological status in determining this context also remains to be characterized.
已知的 5 种黑色素皮质素受体 (MCs) 具有明确的生理作用。除了 MC2 受体之外，这些受体的行为可能无法预测，而且由于它们的表达范围比其既定作用更广泛，因此它们很可能具有其他尚未充分描述的功能。本综述的目的是讨论该受体家族中这 4 个神秘成员（MC1、3-5）的一些研究较少的方面，并描述它们如何成为多功能 G 蛋白偶联受体 (GPCR)。这些受体似乎很杂乱，因为它们结合几种内源性激动剂（前阿黑皮素原 [POMC] 基因的产物）和拮抗剂，但相对亲和力和效果不一致。我们提出，这是由于翻译后修饰决定了受体在纳米域内的定位。在每个纳米域中，都会有多种蛋白质，包括离子通道、修饰蛋白和其他 GPCR，它们可以与 MC 相互作用，改变受体在细胞表面的可用性以及受体激活后的细胞内信号转导。因此，不同的相互作用蛋白和 MC 组合可能会产生报告的 MC 复杂且不一致的功能特征。为了进一步深入了解该家族，需要对组织特异性功能进行更好的表征。目前有证据表明这些受体与一系列伴侣相互作用，从而调节细胞信号转导，这表明应该在其相互作用伴侣的完整背景下研究每个受体。生理状态在确定这种背景中的作用也有待进一步研究。
