title: Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance.
abstract: Membrane microdomains (lipid rafts) are now recognized as critical for proper compartmentalization of insulin signaling. We previously demonstrated that, in adipocytes in a state of TNFalpha-induced insulin resistance, the inhibition of insulin metabolic signaling and the elimination of insulin receptors (IR) from the caveolae microdomains were associated with an accumulation of the ganglioside GM3. To gain insight into molecular mechanisms behind interactions of IR, caveolin-1 (Cav1), and GM3 in adipocytes, we have performed immunoprecipitations, cross-linking studies of IR and GM3, and live cell studies using total internal reflection fluorescence microscopy and fluorescence recovery after photobleaching techniques. We found that (i) IR form complexes with Cav1 and GM3 independently; (ii) in GM3-enriched membranes the mobility of IR is increased by dissociation of the IR-Cav1 interaction; and (iii) the lysine residue localized just above the transmembrane domain of the IR beta-subunit is essential for the interaction of IR with GM3. Because insulin metabolic signal transduction in adipocytes is known to be critically dependent on caveolae, we propose a pathological feature of insulin resistance in adipocytes caused by dissociation of the IR-Cav1 complex by the interactions of IR with GM3 in microdomains.
authors: Division of Glycopathology, Institute of Molecular Biomembranes and Glycobiology, Tohoku Pharmaceutical University, 4-4-1, Komatsushima, Sendai 981-8558, Miyagi, Japan.
authors: Kazuya
authors: K
authors: Kabayama
authors: Takashige
authors: T
authors: Sato
authors: Kumiko
authors: K
authors: Saito
authors: Nicoletta
authors: N
authors: Loberto
authors: Alessandro
authors: A
authors: Prinetti
authors: Sandro
authors: S
authors: Sonnino
authors: Masataka
authors: M
authors: Kinjo
authors: Yasuyuki
authors: Y
authors: Igarashi
authors: Jin-ichi
authors: J
authors: Inokuchi
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D005679:G(M3) Ganglioside / Q000378:metabolism*; D007333:Insulin Resistance; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051242:Caveolin 1; D005679:G(M3) Ganglioside; D011972:Receptor, Insulin; D008239:Lysine
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