Gi-biased β2AR signaling links GRK2 upregulation to heart failure.
Gi-biased β2AR signaling links GRK2 upregulation to heart failure.
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DOI：
10.1161/circresaha.111.253260
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发表时间：
2012-01-20
影响因子：
20.1
通讯作者：
Xiao RP
中科院分区：
文献类型：
--
作者：
Zhu W;Petrashevskaya N;Ren S;Zhao A;Chakir K;Gao E;Chuprun JK;Wang Y;Talan M;Dorn GW 2nd;Lakatta EG;Koch WJ;Feldman AM;Xiao RP
β2-肾上腺素能受体（β 2-adrenergic receptor，β2AR）被丝氨酸/苏氨酸激酶家族G蛋白偶联受体激酶（GRK）和蛋白激酶A（PKA）磷酸化是心脏功能的关键决定因素。G蛋白偶联受体激酶2（GRK 2）的上调是心力衰竭的一个公认的致病因素，但其潜在机制尚不清楚。我们试图确定PKA和GRK介导的β2AR磷酸化对受体偶联Gi信号传导的相对贡献，Gi信号传导减弱心脏储备，并有助于响应压力超负荷的心力衰竭的发病机制。GRK 2过表达可导致培养的小鼠心肌细胞和体内对βAR刺激的收缩反应的Gi依赖性降低。重要的是，缺乏PKA磷酸化位点的突变型β 2 AR（PKA-TG），而不是野生型β 2 AR（WT TG）或缺乏GRK位点的突变型β 2 AR（GRK-TG）的心脏特异性转基因过表达，导致对压力超负荷的过度心脏反应，如显著加剧的心脏适应不良重构和衰竭以及早期死亡所示。此外，在与通过去除受体的PKA磷酸化诱导的β2AR与Gi偶联增加相关的心力衰竭中以及在GRK 2转基因小鼠中，用百日咳毒素抑制Gi信号传导恢复心脏功能，表明GRK增强的β2AR磷酸化以及由此产生的Gi偏向的β2AR信号传导的增加在心力衰竭的发展中起重要作用。我们的数据显示，除了PKA之外，GRK增强的β2AR磷酸化导致受体的Gi偏向信号传导，这反过来有助于心力衰竭的发病机制，标志着Gi偏向的β2AR信号传导是将GRK上调与心脏适应不良重塑、衰竭和心脏抑制联系起来的主要事件。
Phosphorylation of β2-adrenergic receptor (β2AR) by a family of serine/threonine kinases known as G protein-coupled receptor kinase (GRK) and protein kinase A (PKA) is a critical determinant of cardiac function. Upregulation of G protein-coupled receptor kinase 2 (GRK2) is a well-established causal factor of heart failure, but the underlying mechanism is poorly understood. We seek to determine the relative contribution of PKA- and GRK-mediated phosphorylation of β2AR to the receptor coupling to Gi signaling that attenuates cardiac reserve and contributes to the pathogenesis of heart failure in response to pressure overload. Overexpression of GRK2 led to a Gi-dependent decrease of contractile response to βAR stimulation in cultured mouse cardiomyocytes and in vivo. Importantly, cardiac-specific transgenic overexpression of a mutant β2AR lacking PKA phosphorylation sites (PKA- TG), but not the wild type β2AR (WT TG) or a mutant β2AR lacking GRK sites (GRK- TG), led to exaggerated cardiac response to pressure overload, as manifested by markedly exacerbated cardiac maladaptive remodeling and failure, and early mortality. Furthermore, inhibition of Gi signaling with pertussis toxin restores cardiac function in heart failure associated with increased β2AR to Gi coupling induced by removing PKA phosphorylation of the receptor and in GRK2 transgenic mice, indicating that enhanced phosphorylation of β2AR by GRK and resultant increase in Gi-biased β2AR signaling play an important role in the development of heart failure. Our data show that enhanced β2AR phosphorylation by GRK, in addition to PKA, leads the receptor to Gi-biased signaling which, in turn, contributes to the pathogenesis of heart failure, marking Gi-biased β2AR signaling as a primary event linking upregulation of GRK to cardiac maladaptive remodeling, failure and cardiodepression.