Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.
Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies.
复制标题
DOI：
10.1016/j.bbadis.2017.01.020
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Blaxall BC
中科院分区：
文献类型：
--
作者：
Rudomanova V;Blaxall BC
心脏和肾脏之间的病理性串扰被称为心肾综合征（CRS）。虽然这种串扰背后的具体机制仍然知之甚少，但慢性鼻窦炎与一个或两个器官的功能障碍加剧以及生存率降低有关。适应不良的纤维化重塑是心力衰竭和肾衰竭发病机制和进展的关键组成部分。 G 蛋白偶联受体 (GPCR) 信号传导是心血管和肾功能的重要调节因子。慢性/病理性 GPCR 信号传导引发 G 蛋白 Gβγ 亚基与 GPCR 激酶 2 (GRK2) 的相互作用，靶向受体进行内化、病理信号支架和受体降解。针对这种病理性 Gβγ-GRK2 相互作用已被建议作为治疗心力衰竭的可能策略。在当前的综述中，我们讨论了了解 GPCR-Gβγ-GRK2 信号传导作为心力衰竭和肾功能障碍中检测到的适应不良器官重塑的关键介质的作用的最新进展，特别关注小分子介导的病理性 Gβγ-GRK2 相互作用的抑制。此外，我们探索了 GPCR-Gβγ-GRK2 信号传导作为心肾病理的可能治疗靶点的潜力。
The pathologic crosstalk between the heart and kidney is known as cardiorenal syndrome (CRS). While the specific mechanisms underlying this crosstalk remain poorly understood, CRS is associated with exacerbated dysfunction of either or both organs and reduced survival. Maladaptive fibrotic remodeling is a key component of both heart and kidney failure pathogenesis and progression. G-protein coupled receptor (GPCR) signaling is a crucial regulator of cardiovascular and renal function. Chronic/pathologic GPCR signaling elicits the interaction of the G-protein Gβγ subunit with GPCR kinase 2 (GRK2), targeting the receptor for internalization, scaffolding to pathologic signals, and receptor degradation. Targeting this pathologic Gβγ-GRK2 interaction has been suggested as a possible strategy for the treatment of HF. In the current review, we discuss recent updates in understanding the role of GPCR-Gβγ-GRK2 signaling as a crucial mediator of maladaptive organ remodeling detected in HF and kidney dysfunction, with specific attention to small molecule-mediated inhibition of pathologic Gβγ-GRK2 interactions. Further, we explore the potential of GPCR-Gβγ-GRK2 signaling as a possible therapeutic target for cardiorenal pathologies.