心衰患者体内具有高滴度的β1-肾上腺素受体（β1-AR）自身抗体（β1-AA），可抑制β1-AR内吞，导致受体持续激活及心衰的发生，但机制不清。我们前期原创性发现，β2-AR Gi偏向激动剂可缓解β1-AA对β1-AR的持续激活效应，但β1-AA并不直接结合β2-AR。本研究拟在此基础上利用过表达/siRNA、荧光同步成像全内反射显微镜等手段，阐明β2-AR下游Gs/Gi信号转换障碍可引起β1-AR内吞抑制；利用co-IP、融合蛋白等技术，阐明β1/β2-AR异源二聚化减弱是β1-AA引起β2-AR Gs/Gi信号转换障碍的关键机制；利用冷冻电镜、FRET等技术，阐明受体构象改变是β1-AA影响β1/β2-AR异源二聚化的上游机制。以此证明科学假说：β1-AA通过影响β1/β2-AR构象及二聚化，导致β2-AR Gs/Gi转换障碍，β1-AR内吞抑制，进而引起β1-AR持续激活及心衰。

High titer of β1-adrenoreceptor autoantibody (β1-AA) is reported to distribute in heart failure patients, which induces sustained receptor activation and heart failure, while the mechanism still unclear. In the preliminary study, β1-AA, without combining to β2-AR, induced sustained β1-AR activation could be alleviated by Gi-protein biased agonist of β2-AR. On the basis of that, this study aims to explain that the disorder of signaling switch in β2-AR signaling pathway may cause β1-AR endocytosis inhibition by using overexpress/siRNA methods, TIRFM, etc.; demonstrated that weaken β1/β2 heterodimer is one of the mainly mechanisms for the disorder of signaling switch of β2-AR induced by β1-AA via co-Immunoprecipitation and fusion proteins, etc.; certify that β1-AA alters the conformation of both β1 and β2 adrenoreceptor will influence β1/β2 heterodimerization via FRET and Frozen electron microscopy. Therefore, to confirm the scientific hypothesis: β1-AA could cause the disorder of signaling switch of β2-AR, then result in β1-AR endocytosis inhibition and sustained activation, finally develop into heart failure through changing β1 and β2 adrenoreceptor’s conformation and β1/β2 heterodimerization.