Blood pressure is regulated by an α1D-adrenergic receptor/dystrophin signalosome
Blood pressure is regulated by an α1D-adrenergic receptor/dystrophin signalosome
复制标题
DOI：
10.1074/jbc.m801860200
复制
发表时间：
2008-07-04
影响因子：
4.8
通讯作者：
Hague, Chris
中科院分区：
文献类型：
--
作者：
Lyssand, John S.;Defino, Mia C.;Hague, Chris
高血压是一种心血管疾病，与血浆儿茶酚胺增加、交感神经系统过度激活、血管张力增加和总外周阻力有关。α (1D)-肾上腺素能受体（AR）是交感神经系统功能的关键调节因子，属于g蛋白偶联受体（gpcr）肾上腺素能家族。内源性儿茶酚胺，去甲肾上腺素和肾上腺素激活血管平滑肌上的α (1D)-ARs，刺激血管收缩，增加总外周阻力和平均动脉压。事实上，α (1D)-AR KO小鼠表现出低血压表型，并且对盐诱导的高血压具有抗性。不幸的是，由于无法在体外获得功能性表达，关于这种重要的GPCR如何发挥作用的信息很少。在这里，我们确定了肌营养不良蛋白，syntrophin， dystrobrevin和utrophin是α (1D)- ar必需的gpcr相互作用蛋白。我们在体外和体内都发现了与α (1D)-AR复合物的营养不良蛋白，以确保适当的功能表达。更重要的是，我们证明敲除多种syntrophin亚型可导致小鼠主动脉平滑肌细胞α (1D)-AR功能的完全丧失，并消除α (1D)-AR介导的血压升高。我们的研究结果表明，syntrophin和utrophin与α (1D)-AR结合，产生功能性信号体，这对于α (1D)-AR调节血管张力和血压至关重要。
Hypertension is a cardiovascular disease associated with increased plasma catecholamines, overactivation of the sympathetic nervous system, and increased vascular tone and total peripheral resistance. A key regulator of sympathetic nervous system function is the alpha(1D)-adrenergic receptor (AR), which belongs to the adrenergic family of G-protein-coupled receptors (GPCRs). Endogenous catecholamines norepinephrine and epinephrine activate alpha(1D)-ARs on vascular smooth muscle to stimulate vasoconstriction, which increases total peripheral resistance and mean arterial pressure. Indeed, alpha(1D)-AR KO mice display a hypotensive phenotype and are resistant to salt-induced hypertension. Unfortunately, little information exists about how this important GPCR functions because of an inability to obtain functional expression in vitro. Here, we identified the dystrophin proteins, syntrophin, dystrobrevin, and utrophin as essential GPCR-interacting proteins for alpha(1D)-ARs. We found that dystrophins complex with alpha(1D)-AR both in vitro and in vivo to ensure proper functional expression. More importantly, we demonstrate that knock-out of multiple syntrophin isoforms results in the complete loss of alpha(1D)-AR function in mouse aortic smooth muscle cells and abrogation of alpha(1D)-AR-mediated increases in blood pressure. Our findings demonstrate that syntrophin and utrophin associate with alpha(1D)-ARs to create a functional signalosome, which is essential for alpha(1D)-AR regulation of vascular tone and blood pressure.