Permissive action of protein kinase C-ζ in insulin-induced CD36- and GLUT4 translocation in cardiac myocytes

• Published in: Journal of endocrinology Vol. 201; no. 2; pp. 199 - 209
• Main Authors: Luiken, Joost J F P, Ouwens, D Margriet, Habets, Daphna D J, van der Zon, Gerard C M, Coumans, Will A, Schwenk, Robert W, Bonen, Arend, Glatz, Jan F C
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.05.2009
• Subjects: Animals; Biological and medical sciences; CD36 Antigens - metabolism; Cells, Cultured; Enzyme Activation - drug effects; Errors of metabolism; Fatty Acids - metabolism; Glucose Transporter Type 4 - metabolism; Insulin - pharmacology; Male; Medical sciences; Metabolic diseases; Models, Biological; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase C - physiology; Protein Kinase Inhibitors - pharmacology; Protein Transport - drug effects; Proteins and glycoproteins; Rats; Rats, Inbred Lew; Regular papers; Tetradecanoylphorbol Acetate - pharmacology; Heart; Translocation; Pancreatic hormone; Protein kinase C; Enzyme; Transferases; Glycoprotein; GLUT4 gene; Cardiovascular disease; Glucose; Insulin; Uptake; Myocyte; Signal transduction; Heart disease; Circulatory system; Carrier protein
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1677/JOE-09-0046

Insulin stimulates cardiac long-chain fatty acid (LCFA) and glucose uptake via translocation of human homolog of rat fatty acid translocase (CD36) and GLUT4 respectively, from intracellular membrane compartments to the sarcolemma, a process dependent on the activation of phosphatidylinositol-3 kinase. To identify downstream kinases of insulin signaling involved in translocation of CD36 and GLUT4 in the heart, we tested i) which cardiac protein kinase C (PKC) isoforms (α, δ, ε or ζ) are activated by insulin, and ii) whether PKC isoform-specific inhibition affects insulin-stimulated substrate uptake in the heart. Insulin-stimulated LCFA and glucose uptake were completely blunted by inhibition of PKC-ζ, but not by inhibition of conventional or novel PKCs. Concomitantly, translocation of CD36 and GLUT4 to the sarcolemma was completely blunted upon inhibition of PKC-ζ. However, insulin, in contrast to the diacylglycerol-analog phorbol-12-myristate-13-acetate (PMA), did not induce membrane-attachment of the conventional and novel PKCs-α, -δ, and -ε. PKC-ζ was already entirely membrane-bound in non-stimulated cells, and neither insulin nor PMA treatment had any effect on the subcellular localization of PKC-ζ. Furthermore, insulin treatment did not change phosphorylation of PKC-α, -δ, and -ζ or enzymatic activity of PKC-ζ towards a PKC-ζ substrate peptide. It is concluded that PKC-ζ, but not any other PKC isoform, is necessary for insulin-induced translocation of GLUT4 and CD36. However, PKC-ζ is already fully active under basal conditions and not further activated by insulin, indicating that its role in insulin-stimulated uptake of both glucose and LCFA is permissive rather than regulatory.