G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes
| العنوان: | G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes |
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| المؤلفون: | Jerrold M. Olefsky, Jennie L. Babendure, Juu Chin Lu, Christopher J. Hupfeld, Takeshi Imamura, Isao Usui, Hiroaki Satoh |
| المصدر: | Molecular Endocrinology. 19:2760-2768 |
| بيانات النشر: | The Endocrine Society, 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Transcriptional Activation, medicine.medical_specialty, medicine.medical_treatment, Protein Serine-Threonine Kinases, Antibodies, Mice, Endocrinology, Insulin resistance, 3T3-L1 Cells, Internal medicine, Insulin receptor substrate, Adipocytes, Serine, medicine, Animals, Insulin, Phosphorylation, RNA, Small Interfering, Molecular Biology, G protein-coupled receptor kinase, Glucose Transporter Type 4, Endothelin-1, biology, General Medicine, Phosphoproteins, medicine.disease, IRS2, IRS1, Protein Transport, Insulin receptor, Mutation, Insulin Receptor Substrate Proteins, biology.protein, GTP-Binding Protein alpha Subunits, Gq-G11, Insulin Resistance, GLUT4 |
| الوصف: | G protein-coupled receptor kinases (GRKs) regulate seven-transmembrane receptors (7TMRs) by phosphorylating agonist-activated 7TMRs. Recently, we have reported that GRK2 can function as a negative regulator of insulin action by interfering with G protein-q/11 α-subunit (Gαq/11) signaling, causing decreased glucose transporter 4 (GLUT4) translocation. We have also reported that chronic endothelin-1 (ET-1) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and Gαq/11, and decreased insulin-stimulated glucose transport in 3T3-L1 adipocytes. In the current study, we have investigated the role of GRK2 in chronic ET-1-induced insulin resistance. Insulin-induced GLUT4 translocation was inhibited by pretreatment with ET-1 for 24 h, and we found that this inhibitory effect was rescued by microinjection of anti-GRK2 antibody or GRK2 short interfering RNA. We further found that GRK2 mediates the inhibitory effects of ET-1 by two distinct mechanisms. Firstly, adenovirus-mediated overexpression of either wild-type (WT)- or kinase-deficient (KD)-GRK2 inhibited Gαq/11 signaling, including tyrosine phosphorylation of Gαq/11 and cdc42-associated phosphatidylinositol 3-kinase activity. Secondly, ET-1 treatment caused Ser/Thr phosphorylation of IRS-1 and IRS-1 protein degradation. Overexpression of KD-GRK2, but not WT-GRK2, inhibited ET-1-induced serine 612 phosphorylation of IRS-1 and restored activation of this pathway. Taken together, these results suggest that GRK2 mediates ET-1-induced insulin resistance by 1) inhibition of Gαq/11 activation, and this effect is independent of GRK2 kinase activity, and 2) GRK2 kinase activity-mediated IRS-1 serine phosphorylation and degradation. |
| تدمد: | 1944-9917 0888-8809 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d7230a3c2b522fdc5ed8558e930e03c9Test https://doi.org/10.1210/me.2004-0429Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d7230a3c2b522fdc5ed8558e930e03c9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19449917 08888809 |
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