β1受体通过二聚体-单体转换引发心力衰竭时β受体信号异常的机制研究

β肾上腺素受体（β受体）信号异常是心力衰竭（心衰）的基础，但关键问题“心衰时β1受体的儿茶酚胺（CA）敏感性为何降低”尚未阐明。我们已证明β2受体二聚体和单体分别位于细胞膜和细胞质、执行不同功能（Nat Commun 2018）。预实验显示心肌中β1受体以二聚体为主、脚手架蛋白SAP97仅结合β1二聚体；心衰时β1改以单体为主且内吞增加，伴有SAP97减少。据此我们提出假说：β1二聚体和单体间的转换决定了β1受体的CA敏感性。本项目拟采用单分子成像、动物模型、二聚突变体等工具，证明心脏中β1二聚体和单体的功能不同，心衰时SAP97减少导致的β1二聚体-单体转换改变了亚细胞定位，从而引起细胞膜上β1受体CA敏感性降低和细胞质β1-CaMKII等病理信号增强。本项目将阐明心衰时β1受体通过二聚体-单体转换引发β受体信号异常的机制，并证实β1形成二聚体的调控因子SAP97可作为心衰治疗新靶点。

Abnormal signaling of β adrenergic receptor (βAR) is the fundamental of heart failure (HF), however the reason of decreased β1AR catecholamine sensitivity during HF is not fully understood. We have reported that dimeric and monomeric β2AR locate on cell membrane and cytosol separately, with distinct functions (Nat Commun 2018). Further data show that in cardiac myocytes most β1AR form dimers and scaffold protein SAP97 bind with dimeric β1AR exclusively; while during HF most β1AR switch to monomers, which is accompanied with increased β1AR internalization and reduced SAP97 expression. Based on those data we speculate that in the heart the switch between β1AR dimer and monomer determines catecholamine sensitivity of β1AR. This study will use tools including single-molecule imaging, rodent model, and dimeric mutants to prove that dimeric and monomeric β1AR function differently in the heart, during HF the loss of SAP97 promotes β1AR switch from dimer to monomer, which changes β1AR subcellular locations and subsequently cause decreased β1AR catecholamine sensitivity on the cell membrane and up-regulation of pathological signalings such as β1AR-CaMKII in the cytosol. This study will elucidate the mechanism of abnormal β adrenergic signaling caused by β1AR dimer-monomer switch during HF, and prove that the dimeric β1AR switcher SAP97 can be a novel therapeutic target of HF.