Insulin-stimulated glucose uptake in muscle and adipose tissue is primarily mediated by the insulin-responsive glucose transporter isoform, Glut-4. In the basal state, Glut-4 slowly cycles with the majority of the protein sequestered into intracellular storage sites. In response to insulin, the rate of Glut-4 exocytosis becomes markedly increased, resulting in a large accumulation of Glut-4 at the cell surface. Recent findings have suggested that this translocation process may be regulated by Phospholipase D (PLD), a membrane-associated enzyme that is also activated by insulin. PLD catalyzes the hydrolysis of phosphatidylcholine, the most abundant membrane phospholipid, to generate the signaling lipid phosphatidic acid (PA). PA has been proposed to have several cellular functions including the facilitation of membrane vesicle trafficking. There are two mammalian PLD genes, PLD1 and PLD2. We have recently shown that PLD1 facilitates the fusion of neuroendocrine secretory granules into the plasma membrane during regulated exocytosis and that both genes facilitate regulated exocytosis of mast cell histamine-containing granules. Importantly, the fusion mechanisms controlling these secretory granules have many features in common with the insulin-stimulated plasma membrane fusion of Glut-4 vesicles, and we have found recently that PLD1 and PLD2 activation or inhibition alters insulin-stimulated Glut-4 translocation to the plasma membrane. Based upon these novel data, we propose to examine systematically the function of PLD as a key regulatory component in the insulin-stimulated trafficking of Glut-4 by developing reconstitution assays and establishing the role of PLD in physiologically relevant contexts. ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
Zip Code
Huang, Ping; Yeku, Oladapo; Zong, Haihong et al. (2011) Phosphatidylinositol-4-phosphate-5-kinase alpha deficiency alters dynamics of glucose-stimulated insulin release to improve glucohomeostasis and decrease obesity in mice. Diabetes 60:454-63
Yeku, Oladapo; Frohman, Michael A (2011) Rapid amplification of cDNA ends (RACE). Methods Mol Biol 703:107-22
Yeku, Oladapo; Scotto-Lavino, Elizabeth; Frohman, Michael A (2009) Identification of alternative transcripts using rapid amplification of cDNA ends (RACE). Methods Mol Biol 590:279-94
Du, Guangwei; Frohman, Michael A (2009) A lipid-signaled myosin phosphatase surge disperses cortical contractile force early in cell spreading. Mol Biol Cell 20:200-8
Choi, S-Y; Gonzalvez, F; Jenkins, G M et al. (2007) Cardiolipin deficiency releases cytochrome c from the inner mitochondrial membrane and accelerates stimuli-elicited apoptosis. Cell Death Differ 14:597-606
Zhao, Chen; Du, Guangwei; Skowronek, Karl et al. (2007) Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9:706-12
Vicogne, Jerome; Vollenweider, Daniel; Smith, Jeffery R et al. (2006) Asymmetric phospholipid distribution drives in vitro reconstituted SNARE-dependent membrane fusion. Proc Natl Acad Sci U S A 103:14761-6
Huang, Ping; Jiang, Zhirong; Teng, Shuzhi et al. (2006) Synergism between phospholipase D2 and sorbitol accumulation in diabetic cataract formation through modulation of Na,K-ATPase activity and osmotic stress. Exp Eye Res 83:939-48
Corrotte, Matthias; Chasserot-Golaz, Sylvette; Huang, Ping et al. (2006) Dynamics and function of phospholipase D and phosphatidic acid during phagocytosis. Traffic 7:365-77
Scotto-Lavino, Elizabeth; Du, Guangwei; Frohman, Michael A (2006) Amplification of 5' end cDNA with 'new RACE'. Nat Protoc 1:3056-61

Showing the most recent 10 out of 18 publications