Glucose activates prenyltransferases in pancreatic islet beta-cells.
A growing body of evidence implicates small G-proteins [e.g., Cdc42 and Rac1] in glucose-stimulated insulin secretion [GSIS] in the islet beta-cell. These signaling proteins undergo post-translational modifications [e.g., prenylation] at their C-terminal cysteine residue and appear to be essential for the transport and fusion of insulin-containing secretory granules with the plasma membrane and the exocytotic secretion of insulin. However, potential regulation of the prenylating enzymes by physiological insulin secretogues [e.g., glucose] has not been investigated thus far. Herein, we report immunological localization, sub-cellular distribution and regulation of farnesyltransferases [FTases] and geranylgeranyltransferase [GGTase] by glucose in insulin-secreting INS 832/13 beta-cells and normal rat islets. Our findings suggest that an insulinotropic concentration of glucose [20mM] markedly stimulated the expression of the alpha-subunits of FTase/GGTase-1, but not the beta-subunits of FTase or GGTase-1 without significantly affecting the predominantly cytosolic distribution of these holoenzymes in INS 832/13 cells and rodent islets. Under these conditions, glucose significantly stimulated [2.5- to 4.0-fold over basal] the activities of both FTase and GGTase-1 in both cell types. Together, these findings provide the first evidence to suggest that GSIS involves activation of the endogenous islet prenyltransferases by glucose, culminating in the activation of their respective G-protein substrates, which is necessary for cytoskeletal rearrangement, vesicular transport, fusion and secretion of insulin.
Goalstone
Marc
M
Department of Medicine, University of Colorado, VA Medical Center, Denver, CO 80220, USA.
Kamath
Vasudeva
V
Kowluru
Anjaneyulu
A
D019883:Alkyl and Aryl Transferases / Q000096:biosynthesis*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D017368:Protein Prenylation; D051381:Rats
D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D020559:Monomeric GTP-Binding Proteins; D005947:Glucose