Access Type
Open Access Dissertation
Date of Award
January 2024
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Pharmaceutical Sciences
First Advisor
Anjaneyulu Kowluru
Second Advisor
Jiemei Wang
Abstract
Regulation of small GTPases within the pancreatic beta cell is a highly complex and coordinated sequence of protein interactions and post translational modifications. Various families participate in the physiological secretion of insulin in roles ranging from cytoskeletal reorganization to secretory vesicle priming and docking. However the regulatory partners of GTPase function, while studied broadly, lack vital information relating to smgGDS, a protein chaperone of small GTPases to and from the prenylation machinery, and RhoGDI function. Herein these studies are aimed to further our understanding of GTPase regulation and alterations that occur during metabolic stress (glucotoxicity) and related beta cell dysfunction.Data presented show, for the first time, the expression of both smgGDS splice variants within multiple insulin secreting cell lineages and that siRNA mediated depletion of smgGDS significantly decreases glucose-, calcium-, and cAMP-mediated forms of stimulatory insulin secretion. Studies have also presented novel information regarding the expression and nuclear localization of RhoGDI proteins within numerous insulin secreting cell types and that only RhoGDIβ shows an appreciable increase in expression during prolonged periods of metabolic stress, in both whole cell lysates and the nuclear fraction. Previous studies have implicated the cleavage of RhoGDIβ under certain cellular stress conditions, and data presented here show that prolonged exposure to elevated glucose results in increased RhoGDIβ cleavage and translocation of this fragment to the nuclear fraction. These studies have reported novel and significant findings regarding the role of smgGDS in insulin secretion from the pancreatic beta cell and physiologically relevant alterations in the expression and cleavage of RhoGDIβ under prolonged conditions of metabolic stress.
Recommended Citation
Gleason, Noah, "Novel Regulators Of Small G Proteins In The Pancreatic Beta Cell" (2024). Wayne State University Dissertations. 4038.
https://digitalcommons.wayne.edu/oa_dissertations/4038
