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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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タイトル: Endothelin-1 suppresses insulin-stimulated Akt phosphorylation and glucose uptake via GPCR kinase 2 in skeletal muscle cells
その他のタイトル: 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
著者: Horinouchi, Takahiro 著作を一覧する
Hoshi, Akimasa 著作を一覧する
Harada, Takuya 著作を一覧する
Higa, Tsunaki 著作を一覧する
Karki, Sarita 著作を一覧する
Terada, Koji 著作を一覧する
Higashi, Tsunehito 著作を一覧する
Mai, Yosuke 著作を一覧する
Nepal, Prabha 著作を一覧する
Mazaki, Yuichi 著作を一覧する
Miwa, Soichi 著作を一覧する
発行日: 2016年 3月
出版者: Wiley-Blackwell
誌名: British journal of pharmacology
巻: 173
号: 6
開始ページ: 1018
終了ページ: 1032
出版社 DOI: 10.1111/bph.13406
抄録: 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.
資料タイプ: article (author version)
URI: http://hdl.handle.net/2115/64631
出現コレクション:雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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