Glucose Regulates Receptor Glycosylation

Abstract

Vascular smooth muscle cells (VSMCs) respond to changes in extracellular glucose concentration, and exposure to high glucose promotes VSMC responsiveness to angiotensin II (AngII), which may contribute to the vascular complications associated with diabetes. Konishi and Berk show that only in the presence of high glucose do cultured VSMCs exhibit phosphorylation of the kinases Akt and extracellular signal-regulated kinases (ERK1 and ERK2) in response to AngII. AngII, which binds a heterotrimeric GTP-binding protein (G protein)-coupled receptor, may transactivate epidermal growth factor receptors (EGFRs) to mediate stimulation of the Akt and mitogen-activated protein kinase (MAPK) cascades. The authors found that the glycosylation state of EGFR was altered in response to changes in extracellular glucose concentration or in response to the presence of other metabolizable sugars, but not those that were not metabolizable. A time-dependent increase in the presence of a lower-molecular-weight form of EGFR (145 kD rather than 170 kD) appeared when the cells were cultured in low-glucose medium, consistent with glucose consumption. Furthermore, the 145-kD EGFR was not phosphorylated in response to AngII, which is consistent with finding the cells refractory to AngII when cultured in low-glucose medium. Although the 145-kD EGFR was phosphorylated in response to direct ligand binding by either heparin-binding EGF-like growth factor (HB-EGF) or by transforming growth factor-α (TGF-α), this form of the EGFR was not transactivated by G protein-coupled receptor ligands thrombin or sphingosine 1-phosphate. Thus, low glucose appears to promote a change in the glycosylation of the EGFR that alters the receptor's responsiveness to transactivation. The mechanism for this altered transactivation sensitivity may result from a redistribution of the 145-kD form from membrane microdomains, because cells grown in low-glucose medium showed a loss of EGFR from more dense fractions on sucrose density gradients. Thus, altered glycosylation of the EGFR leading to redistribution of the receptors within the plasma membrane may be a mechanism by which metabolic activity of VSMCs controls EGFR transactivation by physiological ligands, such as AngII. A. Konishi, B. C. Berk, Epidermal growth factor receptor transactivation is regulated by glucose in vascular smooth muscle cells. J. Biol. Chem. 278 , 35049-35056 (2003). [Abstract] [Full Text]