Heterodimer of b1-AR and b2-AR Optimizes b-AR Modulation

b1-AR 和 b2-AR 异二聚体优化 b-AR 调制

• 批准号: 7132347
• 负责人: Rui-Ping Xiao
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7132347
• 关键词: adrenergic receptor; biological signal transduction; cardiac myocytes; cell surface receptors; cyclic AMP; dimer; heart contraction; immunoprecipitation; intermolecular interaction; isoproterenol; laboratory mouse; ligands; muscle contraction; protein localization; protein structure function; receptor binding; receptor expression; stimulant /agonist

Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant b-adrenergic receptor (bAR) subtypes expressed in the heart, b1AR and b2AR, and its physiological relevance. In intact adult mouse cardiac myocytes lacking native b1AR and b2AR, co-expression of both bAR subtypes led to receptor heterodimerization, as evidenced by their co-immunoprecipitation, co-localization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to bAR agonist stimulation with isoproterenol (ISO) was shifted leftward by ~1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of bAR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of b1AR greatly suppressed ligand-independent spontaneous activity of co-existing b2ARs. Thus, heterodimerization of b1AR and b2AR in intact cardiac myocytes creates a novel population of bARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing b-adrenergic modulation of cardiac contractility.

相似和不同的 G 蛋白偶联受体亚家族成员之间的分子间相互作用已在各种实验系统中得到证实。在这里，我们证明了心脏中表达的主要 β 肾上腺素能受体 (bAR) 亚型 b1AR 和 b2AR 的异二聚化及其生理相关性。在缺乏天然 b1AR 和 b2AR 的完整成年小鼠心肌细胞中，两种 bAR 亚型的共表达导致受体异二聚化，这通过它们的共免疫沉淀、光学分辨率的共定位以及与亚型选择性配体的结合亲和力显着增加来证明。结果，肌细胞收缩对异丙肾上腺素 (ISO) bAR 激动剂刺激的剂量反应曲线向左移动约 1.5 个数量级，细胞 cAMP 形成对 ISO 的反应也随之增强，表明 bAR 亚型的分子间相互作用导致这些受体对激动剂刺激敏感。相比之下，b1AR 的存在极大地抑制了共存的 b2AR 的配体独立自发活性。因此，完整心肌细胞中 b1AR 和 b2AR 的异二聚化产生了具有独特功能和药理学特性的新型 bAR 群体，从而增强了响应激动剂刺激的信号传导效率，同时沉默了配体非依赖性受体激活，从而优化了心肌收缩力的 β 肾上腺素能调节。