Kristensson Lisbeth, Mayer Gaëll, Ploj Karolina, Wetterlund Martina, Arlbrandt Susanne, Björquist Anna, Wissing Britt-Marie, Castaldo Marie, Larsson Niklas
Discovery Sciences, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
Respiratory, Inflammatory and Autoimmune iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden; Cardiovascular and Metabolic Diseases iMED, AstraZeneca R&D Mölndal, Pepparedsleden 3, S-431 83 Mölndal, Sweden.
Eur J Pharmacol. 2015 Jan 15;747:123-31. doi: 10.1016/j.ejphar.2014.11.041. Epub 2014 Dec 11.
Relaxin family peptide receptor 3 (RXFP3) is a G-protein coupled receptor mainly expressed in the brain and involved in appetite regulation. Previous studies in lean Wistar rats during the light phase have shown that the chimeric peptide R3(BΔ23-27)R/I5 suppresses food intake stimulated by an RXFP3 agonist, but has no effect on food intake when administered alone. We wanted to further investigate if R3(BΔ23-27)R/I5 on its own is able to antagonize the basal tone of the relaxin-3/RXFP3 system and therefore characterized the pharmacology of R3(BΔ23-27)R/I5 in vivo and in vitro. R3(BΔ23-27)R/I5 was intracerebroventricularly (ICV) injected in diet induced obese (DIO) Wistar rats and food intake was automatically measured during the dark phase when feeding drive is high. In our hands, R3(BΔ23-27)R/I5 alone did not have a significant effect on food intake during 24h following administration. Consistent with previous results, relaxin-3 stimulated food intake in satiated lean rats. R3(BΔ23-27)R/I5 was characterized in vitro using [(35)S]-GTPγS binding and cAMP assays, both assessing Gαi-protein mediated signalling, and dynamic mass redistribution (DMR) assays capturing the integrated cell response. R3(BΔ23-27)R/I5 showed partial agonist activity in all three functional assays. Thus, since R3(BΔ23-27)R/I5 displays partial RXFP3 agonist properties in vitro, further in vivo studies including additional tool compounds are needed to address if antagonizing relaxin-3/RXFP3 basal tone is a therapeutically relevant mechanism to regulate food intake and body weight.
松弛素家族肽受体3（RXFP3）是一种主要在大脑中表达且参与食欲调节的G蛋白偶联受体。先前在光照期对瘦的Wistar大鼠进行的研究表明，嵌合肽R3(BΔ23 - 27)R/I5可抑制RXFP3激动剂刺激的食物摄入，但单独给药时对食物摄入无影响。我们想进一步研究R3(BΔ23 - 27)R/I5自身是否能够拮抗松弛素-3/RXFP3系统的基础张力，因此对R3(BΔ23 - 27)R/I5在体内和体外的药理学特性进行了研究。将R3(BΔ23 - 27)R/I5脑室内（ICV）注射到饮食诱导肥胖（DIO）的Wistar大鼠中，并在黑暗期（此时进食驱动力较高）自动测量食物摄入量。在我们的研究中，单独给予R3(BΔ23 - 27)R/I5在给药后的24小时内对食物摄入量没有显著影响。与先前的结果一致，松弛素-3刺激饱腹的瘦大鼠的食物摄入。使用[(35)S]-GTPγS结合和cAMP测定法对R3(BΔ23 - 27)R/I5进行体外特性研究，这两种方法均评估Gαi蛋白介导的信号传导，以及动态质量再分布（DMR）测定法以捕获整合的细胞反应。R3(BΔ23 - 27)R/I5在所有三种功能测定中均表现出部分激动剂活性。因此，由于R3(BΔ23 - 27)R/I5在体外表现出部分RXFP3激动剂特性，需要进一步的体内研究，包括使用其他工具化合物，以确定拮抗松弛素-3/RXFP3基础张力是否是调节食物摄入和体重的治疗相关机制。
