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Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/64631

Title: Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells
Other Titles: Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via G protein-coupled receptor kinase 2 in skeletal muscle cells
Mechanisms for ET-1-induced insulin resistance
Authors: Horinouchi, Takahiro Browse this author →KAKEN DB
Hoshi, Akimasa Browse this author
Harada, Takuya Browse this author
Higa, Tsunaki Browse this author
Karki, Sarita Browse this author
Terada, Koji Browse this author →KAKEN DB
Higashi, Tsunehito Browse this author →KAKEN DB
Mai, Yosuke Browse this author
Nepal, Prabha Browse this author
Mazaki, Yuichi Browse this author
Miwa, Soichi Browse this author →KAKEN DB
Issue Date: Mar-2016
Publisher: Wiley-Blackwell
Journal Title: British journal of pharmacology
Volume: 173
Issue: 6
Start Page: 1018
End Page: 1032
Publisher DOI: 10.1111/bph.13406
Abstract: Background and Purpose: Endothelin-1 (ET-1) reduces insulin-stimulated glucose uptake in skeletal muscle, inducing insulin resistance. Here, we have determined the molecular mechanisms underlying negative regulation by ET-1 of insulin signalling. Experimental Approach: We used the rat L6 skeletal muscle cells fully differentiated into myotubes. Changes in the phosphorylation of Akt was assessed by Western blotting. Effects of ET-1 on insulin-stimulated glucose uptake was assessed with [3H]-2-deoxy-d-glucose ([3H]2-DG). The C-terminus region of GPCR kinase 2 (GRK2-ct), a dominant negative GRK2, was overexpressed in L6 cells using adenovirus-mediated gene transfer. GRK2 expression was suppressed by transfection of the corresponding short-interfering RNA (siRNA). Key Results: In L6 myotubes, insulin elicited sustained Akt phosphorylation at Thr308 and Ser473, which was suppressed by ET-1. The inhibitory effects of ET-1 were prevented by treatment with a selective ETA receptor antagonist and a Gq protein inhibitor, overexpression of GRK2-ct and knockdown of GRK2. Insulin increased [3H]2-DG uptake rate in a concentration-dependent manner. ET-1 noncompetitively antagonized insulin-stimulated [3H]2-DG uptake. Blockade of ETA receptors, overexpression of GRK2-ct and knockdown of GRK2 prevented the ET-1-induced suppression of insulin-stimulated [3H]2-DG uptake. In L6 myotubes overexpressing FLAG-tagged GRK2, ET-1 facilitated the interaction of endogenous Akt with FLAG-GRK2. Conclusions and Implications: Activation of ETA receptors with ET-1 suppressed insulin-induced Akt phosphorylation at Thr308 and Ser473 and [3H]2-DG uptake in a GRK2-dependent manner in skeletal muscle cells. These findings suggest that ETA receptors and GRK2 are potential targets for overcoming insulin resistance.
Rights: This is the peer reviewed version of the following article: Horinouchi, T., Hoshi, A., Harada, T., Higa, T., Karki, S., Terada, K., Higashi, T., Mai, Y., Nepal, P., Mazaki, Y., and Miwa, S. (2016) Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells. British Journal of Pharmacology, 173: 1018–1032, which has been published in final form at http://dx.doi.org/10.1111/bph.13406. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Type: article (author version)
URI: http://hdl.handle.net/2115/64631
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 堀之内 孝広

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