Underappreciated roles for Rho GDP dissociation inhibitors (RhoGDIs) in cell function: Lessons learned from the pancreatic islet β-cell

Rho subfamily of G proteins (e.g., Rac1) have been implicated in glucose-stimulated insulin secretion from the pancreatic beta-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 beta-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 (RhoGDI alpha, RhoGDI beta and RhoGDI gamma) 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 beta-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 beta-cell mass under the duress of metabolic stress are highlighted.

Automated summary

The Rho subfamily of G proteins, particularly Rac1, plays a crucial role in glucose-stimulated insulin secretion from pancreatic beta-cells. Metabolic stress, such as chronic exposure to high glucose, can lead to sustained activation of Rac1, resulting in oxidative stress, impaired insulin secretion, and beta-cell dysfunction. The regulation of G protein activation and deactivation is mediated by GEFs, GAPs, and GDIs, with GDIs playing essential roles in G protein function and subcellular targeting for effector activation and cell regulation.