G protein-coupled receptor kinases in normal and failing myocardium.
G protein-coupled receptor kinases in normal and failing myocardium.
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DOI：
10.2741/3898
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发表时间：
2011-06-01
期刊：
影响因子：
--
通讯作者：
Koch WJ
中科院分区：
文献类型：
--
作者：
Huang ZM;Gold JI;Koch WJ
心力衰竭（HF）是许多潜在心血管疾病的终末期，是工业化国家发病率和死亡率的主要原因之一。HF的显著特征之一是G蛋白偶联受体（GPCR）信号转导系统，特别是β-肾上腺素能受体（βAR）系统的脱敏。GPCR脱敏是由GPCR激酶（GRKs）磷酸化启动的，随后是下调和与其G蛋白的功能解偶联。在心脏中，主要的GRK同种型GRK 2和GRK 5由于交感神经系统活性升高而经历上调，这是HF的特征，因为儿茶酚胺水平增加以努力驱动衰竭的泵。这种脱敏导致心力衰竭的变力储备和功能能力的明显丧失。此外，GRK 2和GRK 5具有增加的非GPCR相互作用组，这可能在心脏生理学中起关键作用。本文就GRKs的经典GPCR激酶功能、GRKs的新型非GPCR激酶活性、它们在心肌肥厚和心力衰竭发病机制中的作用以及GRKs作为未来药物靶点的可能性进行综述。
Heart failure (HF) is the end stage of many underlying cardiovascular diseases and is among the leading causes of morbidity and mortality in industrialized countries. One of the striking characteristics of HF is the desensitization of G protein-coupled receptor (GPCR) signaling, particularly the β-adrenergic receptor (βAR) system. GPCR desensitization is initiated by phosphorylation by GPCR kinases (GRKs), followed by downregulation and functional uncoupling from their G proteins. In the heart, the major GRK isoforms, GRK2 and GRK5, undergo upregulation due to the heightened sympathetic nervous system activity that is characteristic of HF as catecholamine levels increase in an effort to drive the failing pump. This desensitization leads to the distinctive loss of inotropic reserve and functional capacity of the failing heart. Moreover, GRK2 and GRK5 have an increasing non-GPCR interactome, which may play critical roles in cardiac physiology. In the current review, the canonical GPCR kinase function of GRKs and the novel non-GPCR kinase activity of GRKs, their contribution to the pathogenesis of cardiac hypertrophy and HF, and the possibility of GRKs serving as future drug targets will be discussed.
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64.8
作者：
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