Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Dupage Medical Technology, Inc., Chicago, IL, 60612, USA.
Nat Commun. 2023 Aug 16;14(1):4966. doi: 10.1038/s41467-023-40531-3.
The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα-p115RhoGEF interaction. Furthermore, whereas β deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a β-derived Gα-binding peptide or Gα knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the β-derived Gα-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.
整合素和 G 蛋白偶联受体在细胞生物学中都很基础。然而，这两者之间的串扰尚不清楚。在这里，我们表明β整合素通过直接抑制 Gα-p115RhoGEF 相互作用，负调控 G 蛋白偶联信号转导。此外，尽管β缺陷或整合素拮抗剂抑制整合素依赖性血小板聚集和胞吐作用（颗粒分泌），但它们增强了 G 蛋白偶联 RhoA 激活和整合素非依赖性分泌。相反，β衍生的 Gα 结合肽或 Gα 敲除抑制 G 蛋白偶联 RhoA 激活以及整合素非依赖性和依赖性血小板分泌，而不影响原发性血小板聚集。在体内心肌缺血/再灌注损伤的小鼠模型中，β衍生的 Gα 结合肽抑制血小板颗粒成分的分泌，这加剧了炎症和缺血/再灌注损伤。这些数据确立了至关重要的整合素- G 蛋白串扰，为治疗方法提供了依据，这些方法可以抑制血小板和其他细胞的胞吐作用，而不会产生与细胞黏附丧失相关的不良反应。
