title: Diacylglycerol kinase δ1 transiently translocates to the plasma membrane in response to high glucose.
abstract: The type II diacylglycerol kinases (DGKs) contain several functional domains such as a pleckstrin homology (PH) domain, two C1 domains and a sterile α-motif (SAM) domain. It was previously revealed that DGKδ contributes to hyperglycemia-induced peripheral insulin resistance and thereby exacerbate the severity of type 2 diabetes. Moreover, a high extracellular concentration of glucose activated DGKδ in skeletal muscle cells, which was followed by a reduction in the intracellular diacylglycerol levels and the inactivation of protein kinase Cα, the enzyme that phosphorylates and inactivates the insulin receptor. However, the intracellular behavior of DGKδ upon high glucose stimulation remains unclear. In this study, we found that DGKδ1, but not a splice variant DGKδ2 or the other type II DGKη1/2, translocated from the cytoplasm to the plasma membrane in human embryonic kidney HEK293 and mouse myoblast C2C12 cells within 5 min in response to high glucose levels. The translocation was inhibited by phosphatidylinositol 3-kinase inhibitors, LY294002 and GDC-0941, suggesting that the event is regulated via the phosphatidylinositol 3-kinase pathway. Moreover, we revealed that the PH and C1 domains are responsible for the plasma membrane translocation and that the SAM domain negatively regulates the translocation. These results indicate that DGKδ1 is the sole type II DGK isoform that responds rapidly and dynamically to high glucose levels.
authors.affiliation: Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Shizuka
authors.initials: S
authors.lastname: Sakiyama
authors.forename: Takako
authors.initials: T
authors.lastname: Usuki
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sakai
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakane
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects*; D013549:Sweetening Agents / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D013549:Sweetening Agents; D019852:Diacylglycerol Kinase; D005947:Glucose