Biomedical Research Service, John D. Dingell VA Medical Center and Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Biomedical Research Service, John D. Dingell VA Medical Center and Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Biochem Pharmacol. 2022 Mar;197:114886. doi: 10.1016/j.bcp.2021.114886. Epub 2021 Dec 28.
Rho subfamily of G proteins (e.g., Rac1) have been implicated in glucose-stimulated insulin secretion from the pancreatic β-cell. Interestingly, metabolic stress (e.g., chronic exposure to high glucose) results in sustained activation of Rac1 leading to increased oxidative stress, impaired insulin secretion and β-cell dysfunction. Activation-deactivation of Rho G proteins is mediated by three classes of regulatory proteins, namely the guanine nucleotide exchange factors (GEFs), which facilitate the conversion of inactive G proteins to their active conformations; the GTPase-activating proteins (GAPs), which convert the active G proteins to their inactive forms); and the GDP-dissociation inhibitors (GDIs), which prevent the dissociation of GDP from G proteins. Contrary to a large number of GEFs (82 members) and GAPs (69 members), only three members of RhoGDIs (RhoGDIα, RhoGDIβ and RhoGDIγ) are expressed in mammalian cells.Even though relatively smaller in number, the GDIs appear to play essential roles in G protein function (e.g., subcellular targeting) for effector activation and cell regulation. Emerging evidence also suggests that the GDIs are functionally regulated via post-translational modification (e.g., phosphorylation) and by lipid second messengers, lipid kinases and lipid phosphatases. We highlight the underappreciated regulatory roles of RhoGDI-Rho G protein signalome in islet β-cell function in health and metabolic stress. Potential knowledge gaps in the field, and directions for future research for the identification of novel therapeutic targets to loss of functional β-cell mass under the duress of metabolic stress are highlighted.
Rho 亚家族 G 蛋白（如 Rac1）已被牵连到胰腺β细胞的葡萄糖刺激胰岛素分泌中。有趣的是，代谢应激（如长期暴露于高葡萄糖）导致 Rac1 的持续激活，从而导致氧化应激增加、胰岛素分泌受损和β细胞功能障碍。Rho G 蛋白的激活-失活由三类调节蛋白介导，即鸟嘌呤核苷酸交换因子（GEFs），它促进无活性 G 蛋白转化为其活性构象；GTPase 激活蛋白（GAPs），将活性 G 蛋白转化为无活性形式；以及 GDP 解离抑制剂（GDIs），防止 GDP 从 G 蛋白解离。与大量的 GEFs（82 个成员）和 GAPs（69 个成员）相反，哺乳动物细胞中仅表达三种 RhoGDIs（RhoGDIα、RhoGDIβ 和 RhoGDIγ）。尽管数量相对较少，但 GDIs 似乎在 G 蛋白功能（例如效应器激活和细胞调节的亚细胞靶向）中发挥重要作用。新出现的证据还表明，GDIs 通过翻译后修饰（例如磷酸化）以及通过脂质第二信使、脂质激酶和脂质磷酸酶来进行功能调节。我们强调了在健康和代谢应激下胰岛β细胞功能中被低估的 RhoGDI-Rho G 蛋白信号转导的调节作用。突出了该领域中尚未被充分认识的知识空白，并为未来的研究指明了方向，以确定在代谢应激下功能性β细胞数量减少的新型治疗靶点。
