インスリン受容体と三量体型GTP結合タンパク質Gq共役受容体シグナル伝達系間のクロストークに関する研究

Insulin exerts diverse physiological effects, which are mediated by its specific receptor with intrinsic protein tyrosine kinase activity. On the other hand, heterotrimeric G-proteins, consisting of α, β and γ subunits, are coupled to specific receptors for many ligands, and transmit the signal to the downstream effectors. Kishi et al. have already reported that stimulation of Gq-coupled receptors can induce GLUT 4 (glucose transporter type 4) translocation to the cell surface in an insulin-independent manner in CHO cells and 3T3-L1 adipocytes. In this study, we have established CHO (Chinese hamster ovary) cells stably expressing Gq-coupled bradykinin receptors, in order to examine crosstalks between insulin- and G-protein-coupled receptor-mediated signal transduction pathways.
Insulin enhanced insulin receptor kinase activity, IRS-1 (insulin receptor substrate-1) tyrosine phosphorylation, PI 3-kinase and Akt kinase activities, and glycogen synthesis, and induced GLUT 4 translocation in this cell line. Bradykinin treatment inhibited the insulin-stimulated receptor kinase activity, IRS-1 phosphorylation, PI 3-kinase and Akt kinase activities, and glycogen synthesis, while bradykinin itself had no effects on the insulin receptor kinase, IRS-1, PI3-kinase, Akt kinase, and glycogen synthesis. These results showed that Gq signaling interferes insulin receptor signaling at least in the early step (s) including insulin receptor kinase activation. The Gq-mediated inhibition of insulin signal may explain some insulin resistant states appeared in non-insulin-dependent diabetes mellitus.