GRK4/PP2A竞争性调节AT1受体磷酸化在高血压发生中的作用研究

G protein-coupled receptor kinase 4 (GRK4) plays a key role in vascular activity and hypertension, via regulating the G protein coupled receptors (including dopamine receptors, endothelin B receptor and so on) expression and phosphorylation. Interestingly, our previous studies found that GRK4, as one kind of kinase, leads to the dephosphorylation of AT1 receptor, which ascribe to the decreasing interaction between GRK4 and AT1 receptor in hypertension. However, the mechanisms of decreasing interaction between GRK4 and AT1 receptor are still unclear. Besides, protein phosphatase 2A (PP2A) dephosphorylates AT1 receptor. Our studies also proved that PP2A/GRK4 and AT1 receptor shows colocalization in VSMC; while the interaction of PP2A and AT1 receptor is increasing, the interaction of GRK4 and AT1 receptor is decreasing in hypertension. And the protein interaction prediction shows that the 253-284 AA of AT1 receptor amino acid sequence is the co-binding sites of PP2A-AT1 receptor and GRK4-AT1 receptor. PP2A activity is also increased in hypertension. Thus, we infer that PP2A and GRK4 co-regulates the phosphorylation of AT1 receptor via the competitive binding, and the unbalance of GRK4 and PP2A dephosphorylates AT1 receptor and leading to hypertension. The present study indicates a new mechanism of AT1 receptor in pathogenesis of hypertension, and which may be an effective therapeutic target for essential hypertension.

GRK4通过调节众多G蛋白偶联受体的表达和磷酸化水平在血管舒缩和高血压发生中发挥重要的作用。我们前期工作发现：GRK4作为磷酸化的激酶却导致了AT1受体去磷酸化；初步发现其发生与高血压状态下GRK4与AT1受体连接程度降低有关，但导致该连接程度下降的原因尚不清楚。同样对AT1受体磷酸化具有调控作用的PP2A引起我们的关注，我们发现高血压状态下，AT1受体与GRK4的结合下降，而AT1受体与PP2A的结合升高。生物信息学研究显示AT1受体在253-284氨基酸残基区域内存在多个可与GRK4及PP2A结合的共同位点，由于高血压状态下PP2A表达和活性增加，我们推测：PP2A与GRK4竞争性调节AT1受体磷酸化，PP2A与GRK4的作用失衡使AT1受体呈低磷酸化，促进了高血压的发生、发展。此问题的解决将为阐明AT1受体在高血压致病中的作用机制做出有益的尝试，为高血压治疗提供理论基础。

GRK4通过调节众多G蛋白偶联受体的表达和磷酸化水平在血管舒缩和高血压发生中发挥重要的作用。我们前期工作发现：GRK4作为磷酸化的激酶却导致了AT1受体去磷酸化；初步发现其发生与高血压状态下GRK4与AT1受体连接程度降低有关，但导致该连接程度下降的原因尚不清楚。本项目的研究发现，高血压状态下，动脉PP2A活性显著增加， AT1受体与GRK4的相互作用下降，但其与PP2A的结合增加，二者之间可能存在相互竞争。GRK4过表达的情况下PP2A的表达增加，而降低GRK4表达可减少PP2A的表达。干扰GRK4表达的情况下，血管平滑肌A10细胞AT1受体与PP2A的相互作用显著增加，而在GRK4过表达的GRK4 142V A10细胞中AT1受体与PP2A的相互作用下降。PP2A与GRK4间存在相互作用，共同影响了AT1受体的功能。抑制血管环组织的PP2A活性，血管对Ang-II的反应性显著下降， PP2A抑制剂LB-100增加了坎地沙坦的降压作用。W253，T260和I279可能是AT1受体与GRK4及PP2A的结合位点。此问题的解决将为阐明GRK4及AT1受体在高血压致病中的作用机制做出有益的尝试。在这一研究基础上，本课题聚焦GRK4在高血压发生中的核心作用，对GRK4的内源性抑制剂进行探索，发现了肌肉因子irisin可通过抑制GRK4发挥降低血压的作用，为高血压治疗提供理论基础。

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