Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
J Mol Endocrinol. 2013 Jun 29;51(1):109-18. doi: 10.1530/JME-13-0061. Print 2013.
Obesity is one of the most challenging global health problems. One key player in energy homeostasis is the melanocortin-4 receptor (MC4R), which is a family A G-protein-coupled receptor (GPCR). It has recently been shown that MC4R has the capacity to form homo- or heterodimers. Dimerization of GPCRs is of great importance for signaling regulation, with major pharmacological implications. Unfortunately, not enough is yet known about the detailed structural properties of MC4R dimers or the functional consequences of receptor dimerization. Our goal, therefore, was to explore specific properties related to MC4R dimerization. First, we aimed to induce the dissociation of dimers to monomers and to compare the functional parameters of wild-type and MC4R variants. To inhibit homodimerization, we designed MC4R chimeras with the cannabinoid-1 receptor, a receptor that does not interact with MC4R. Indeed, we identified several substitutions in the intracellular loop 2 (ICL2) and adjacent regions of transmembrane helix 3 (TMH3) and TMH4 that lead to partial dimer dissociation. Interestingly, the capacity for signaling activity was generally increased in these MC4R variants, although receptor expression remained unchanged. This increase in activity for dissociated receptors might indicate a link between receptor dimerization and signaling capacity. Moreover, dimer dissociation was also observed in a naturally occurring activating MC4R mutation in ICL2. Taken together, this study provides new information on the structural prerequisites for MC4R dimerization and identifies an approach to induce the dissociation of MC4R dimers. This might be useful for further investigation of pharmacological properties.
肥胖是全球面临的最严峻的健康挑战之一。在能量平衡中，黑皮质素 4 受体（MC4R）是一个关键调节因子，它是 A 类 G 蛋白偶联受体（GPCR）家族的一员。最近有研究表明 MC4R 能够形成同源或异源二聚体。GPCR 二聚化对于信号调节非常重要，具有重要的药理学意义。不幸的是，目前对于 MC4R 二聚体的详细结构特性或受体二聚化的功能后果还知之甚少。因此，我们的目标是探索与 MC4R 二聚化相关的特定性质。首先，我们旨在诱导二聚体解离为单体，并比较野生型和 MC4R 变体的功能参数。为了抑制同源二聚化，我们设计了含有大麻素 1 受体（CB1R）的 MC4R 嵌合体，CB1R 与 MC4R 不相互作用。事实上，我们在细胞内环 2（ICL2）和跨膜螺旋 3（TMH3）和 TMH4 的相邻区域鉴定出几个取代，这些取代导致部分二聚体解离。有趣的是，这些 MC4R 变体的信号活性能力通常增加，尽管受体表达保持不变。这种分离的受体的活性增加可能表明受体二聚化和信号转导能力之间存在联系。此外，在 ICL2 中的一种自然发生的激活型 MC4R 突变中也观察到二聚体解离。总之，本研究为 MC4R 二聚化的结构前提提供了新的信息，并确定了诱导 MC4R 二聚体解离的方法。这对于进一步研究药理学特性可能很有用。
