PDF(Pubmed)
Abstract：
Inflammatory hyperalgesia represents a nociceptive phenotype that can become persistent in nature through dynamic protein modifications. However, a large gap in knowledge exists concerning how the integration of intracellular signaling molecules coordinates a persistent inflammatory phenotype. Herein, we demonstrate that Raf Kinase Anchoring Protein (RKIP) interrupts a vital canonical desensitization pathway to maintain bradykinin (BK) receptor activation in primary afferent neurons. Biochemical analyses of primary neuronal cultures indicate bradykinin-stimulated PKC phosphorylation of RKIP at Ser153. Furthermore, BK exposure increases G-protein Receptor Kinase 2 (GRK2) binding to RKIP, inhibiting pharmacological desensitization of the BK receptor. Additional studies found that molecular RKIP down-regulation increases BK receptor desensitization in real-time imaging of primary afferent neurons, identifying a key pathway integrator in the desensitization process that controls multiple GRK2-sensitive G-protein coupled receptors. Therefore, RKIP serves as an integral scaffolding protein that inhibits BK receptor desensitization.
摘要：
炎性痛觉过敏代表一种伤害性表型,其可通过动态蛋白质修饰而在自然界中变得持久。然而,关于细胞内信号分子的整合如何协调持续性炎症表型的知识存在很大差距.在这里，我们证明了Raf激酶锚定蛋白（RKIP）中断了重要的经典脱敏途径，以维持初级传入神经元中缓激肽（BK）受体的激活。原代神经元培养物的生化分析表明缓激肽刺激的PKC在Ser153处磷酸化RKIP。此外，BK暴露会增加G蛋白受体激酶2（GRK2）与RKIP的结合，抑制BK受体的药理学脱敏。其他研究发现，分子RKIP下调增加BK受体脱敏在初级传入神经元的实时成像，确定脱敏过程中控制多个GRK2敏感G蛋白偶联受体的关键途径整合者。因此,RKIP充当抑制BK受体脱敏的完整支架蛋白。
