title: Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes.
abstract: The insulin receptor-independent insulin-mimetic signalling provoked by the antidiabetic sulfonylurea drug, glimepiride, is accompanied by the redistribution and concomitant activation of lipid raft-associated signalling components, such as the acylated tyrosine kinase, pp59(Lyn), and some glycosylphosphatidylinositol-anchored proteins (GPI-proteins). We now found that impairment of glimepiride-induced lipolytic cleavage of GPI-proteins in rat adipocytes by the novel inhibitor of glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), GPI-2350, caused almost complete blockade of (i) dissociation from caveolin-1 of pp59(Lyn) and GPI-proteins, (ii) their redistribution from high cholesterol- (hcDIGs) to low cholesterol-containing (lcDIGs) lipid rafts, (iii) tyrosine phosphorylation of pp59(Lyn) and insulin receptor substrate-1 protein (IRS-1) and (iv) stimulation of glucose transport as well as (v) inhibition of isoproterenol-induced lipolysis in response to glimepiride. In contrast, blockade of the moderate insulin activation of the GPI-PLC and of lipid raft protein redistribution by GPI-2350 slightly reduced insulin signalling and metabolic action, only. Importantly, in response to both insulin and glimepiride, lipolytically cleaved hydrophilic GPI-proteins remain associated with hcDIGs rather than redistribute to lcDIGs as do their uncleaved amphiphilic versions. In conclusion, GPI-PLC controls the localization within lipid rafts and thereby the activity of certain GPI-anchored and acylated signalling proteins. Its stimulation is required and may even be sufficient for insulin-mimetic cross-talking to IRS-1 in response to glimepiride via redistributed and activated pp59(Lyn).
authors.affiliation: Sanofi-Aventis, TD Metabolism, Industrial Park Frankfurt-Höchst, 65926 Frankfurt am Main, Germany. guenter.Mueller@sanofi-aventis.com
authors.forename: Günter
authors.initials: G
authors.lastname: Müller
authors.forename: Andrea
authors.initials: A
authors.lastname: Schulz
authors.forename: Susanne
authors.initials: S
authors.lastname: Wied
authors.forename: Wendelin
authors.initials: W
authors.lastname: Frick
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D008066:Lipolysis; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis*; D051381:Rats; D015398:Signal Transduction; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D017261:Glycosylphosphatidylinositols; D007328:Insulin; D008565:Membrane Proteins; D013453:Sulfonylurea Compounds; C057619:glimepiride; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010738:Type C Phospholipases