Date of Award
Doctor of Philosophy (PhD)
Post-translational processing is critical for the appropriate subcellular localization and function of platelet G-proteins. The majority of the platelet responses to agonists are mediated through specific receptor/G-protein complexes. Therefore, G-protein activity is central to "normal" platelet activity (i.e. aggregation). We have shown that Simvastatin, the in vivo inhibitor of HMG CoA Reductase and therefore isoprenoid synthesis, inhibits the post-translational processing of specific platelet G-proteins and alters platelet responses to agonists. These results show the importance of post-translational processing of G-proteins to platelet activity. Altered post-translational processing of specific G-proteins may explain platelet hyperactivity and the increased incidence of cardiovascular disease in diabetes. Our lab previously reported an increase in platelet rap 1B activity in non-insulin dependent diabetes mellitus (NIDDM), with no increase in rap 1B concentration. A central player in the signal transduction pathways of platelet activation, the low molecular weight, ras-related G-protein rap 1B transduces signals for the activation of phospholipase C and cytoskeletal reorganization in platelets. Our results show that in resting platelets in NIDDM, the majority of rap 1B is fully processed, while rap 1B in resting platelets from healthy controls is predominantly non-processed. Further experiments indicated that carboxy-methylation of platelet rap 1B is activation-dependent in normal healthy individuals. These results suggest that post-translational processing of platelet rap 1B in NIDDM is not under the "normal" constraints of regulation. Carboxy-methylation assays using enzyme from control and NIDDM platelets indicated an increase in both basal and stimulated carboxy methyltransferase activity in NIDDM. Carboxy-methylation seemed to be "stimulated" in resting platelets in NIDDM, and this defect was compounded by platelet activation. Therefore, increased processing and activity of platelet rap 1B in NIDDM can be explained by increased carboxy-methylation in NIDDM platelets.
Hall, Elizabeth A..
"Abnormalities in Post-Translational Processing of Platelet Rap 1B in NIDDM: A Possible Cause of Platelet Hyperactivity and Cardiovascular Disease in Diabetes"
(1997). Doctor of Philosophy (PhD), dissertation, , Old Dominion University, DOI: 10.25777/a5je-8k81