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Novel regulation of adrenomedullin receptor by PDGF: role of receptor activity modifying protein-3.

机译:PDGF对肾上腺髓质素受体的新调节:受体活性修饰蛋白3的作用。

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摘要

Receptor activity modifying protein-3 (RAMP-3) has been shown to complex with the calcitonin receptor-like receptor, establishing a functional receptor for adrenomedullin (AM). AM exhibits potent antiproliferative and antimigratory effects on rat mesangial cells (RMCs). In this study we investigated the effect of platelet-derived growth factor (PDGF) on RAMP-3 expression in RMCs. We show here that PDGF-BB stimulates RAMP-3 mRNA expression in a concentration-dependent manner. Pretreatment with actinomycin-D and alpha-amanitin demonstrates that this effect is independent of new RNA synthesis. Furthermore, PDGF increased the half-life of RAMP-3 mRNA from 66.5 to 331.6 min. Using selective inhibitors, our results also indicate that the increase in RAMP-3 mRNA is mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK and p38 MAPK dependent. PDGF also caused a corresponding elevation in membrane-associated RAMP-3 protein. Associated with this increase, PDGF pretreatment led to a significantly higher AM-mediated adenylate cyclase activity, suggesting a functional consequence for the PDGF-induced increase in RAMP-3 expression. Taken together, these data identify PDGF-dependent regulation of RAMP-3 expression as a possible mechanism for modulating the responsiveness of the mesangial cell to AM.
机译:受体活性修饰蛋白3(RAMP-3)已与降钙素受体样受体复合,建立了肾上腺髓质素(AM)的功能性受体。 AM对大鼠系膜细胞(RMC)表现出强效的抗增殖和抗迁移作用。在这项研究中,我们调查了血小板衍生生长因子(PDGF)对RMC中RAMP-3表达的影响。我们在这里显示PDGF-BB以浓度依赖的方式刺激RAMP-3 mRNA表达。用放线菌素-D和α-amanitin预处理表明,这种作用与新的RNA合成无关。此外,PDGF将RAMP-3 mRNA的半衰期从66.5分钟增加至331.6分钟。使用选择性抑制剂,我们的结果还表明,RAMP-3 mRNA的增加是有丝分裂原激活的蛋白激酶(MAPK)激酶(MEK)/ MAPK和p38 MAPK依赖性的。 PDGF还引起与膜相关的RAMP-3蛋白的相应升高。与这种增加相关的是,PDGF预处理导致AM介导的腺苷酸环化酶活性明显更高,提示PDGF诱导的RAMP-3表达增加的功能性结果。综上所述,这些数据确定了PDGF对RAMP-3表达的依赖性调节,这可能是调节系膜细胞对AM应答的可能机制。

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