Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic beta cell.
Recent findings have implicated post-translational modifications at C-terminal cysteines [e.g., methylation] of specific proteins [e.g., G-proteins] in glucose-stimulated insulin secretion [GSIS]. Furthermore, methylation at the C-terminal leucine of the catalytic subunit of protein phosphatase 2A [PP2Ac] has also been shown to be relevant for GSIS. In addition to these two classes of protein methyl transferases, a novel class of glucose-activated phospholipid methyl transferases have also been identified in the beta cell. These enzymes catalyze three successive methylations of phosphatidylethanolamine to yield phosphatidylcholine. The "newly formed" phosphatidylcholine is felt to induce alterations in the membrane fluidity, which might favor vesicular fusion with the plasma membrane for the exocytosis of insulin. The objectives of this commentary are to: (i) review the existing evidence on the regulation, by glucose and other insulin secretagogues, of post-translational carboxylmethylation [CML] of specific proteins in the beta cell; (ii) discuss the experimental evidence, which implicates regulation, by glucose and other insulin secretagogues, of phosphatidylethanolamine methylation in the islet beta cell; (iii) propose a model for potential cross-talk between the protein and lipid methylation pathways in the regulation of GSIS and (iv) highlight potential avenues for future research, including the development of specific pharmacological inhibitors to further decipher regulatory roles for these methylation reactions in islet beta cell function.
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University and beta Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Detroit, MI 48201, United States. akowluru@med.wayne.edu
Anjaneyulu
A
Kowluru
D000818:Animals; D001120:Arginine / Q000378:metabolism; D003553:Cystine / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008745:Methylation; D010743:Phospholipids / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D011506:Proteins / Q000378:metabolism*
D007328:Insulin; D010743:Phospholipids; D011506:Proteins; D003553:Cystine; D001120:Arginine; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D019204:GTP-Binding Proteins; D007930:Leucine; D005947:Glucose