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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064166-04
Application #
7060866
Study Section
Metabolism Study Section (MET)
Program Officer
Blondel, Olivier
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$257,186
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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