Dissociation of the Insulin Receptor and Caveolin-1 Complex by Ganglioside GM3 in the State of Insulin Resistance

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Aug 19

PMID 17699617

Citations 153

Authors

Kazuya Kabayama

Takashige Sato

Kumiko Saito

Nicoletta Loberto

Alessandro Prinetti

Sandro Sonnino

Masataka Kinjo

Yasuyuki Igarashi

Jin-Ichi Inokuchi

Affiliations

Soon will be listed here.

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.

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