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

Isao Usui, Takeshi Imamura, Jennie Bever, Hiroaki Satoh, Juu Chin Lu, Christopher J. Hupfeld, Jerrold M. Olefsky

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2760-2768
Number of pages9
JournalMolecular Endocrinology
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

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G-Protein-Coupled Receptor Kinase 2
Insulin Receptor Substrate Proteins
Endothelin-1
Adipocytes
Insulin Resistance
Phosphorylation
Phosphotransferases
Insulin
Facilitative Glucose Transport Proteins
Serine
Tyrosine
G-Protein-Coupled Receptor Kinases
Phosphatidylinositol 3-Kinase
Microinjections
GTP-Binding Proteins
Adenoviridae
Small Interfering RNA
Proteolysis
Anti-Idiotypic Antibodies
Glucose

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Usui, Isao; Imamura, Takeshi; Bever, Jennie; Satoh, Hiroaki; Lu, Juu Chin; Hupfeld, Christopher J.; Olefsky, Jerrold M.

In: Molecular Endocrinology, Vol. 19, No. 11, 01.11.2005, p. 2760-2768.

Research output: Contribution to journalArticle

Usui, Isao ; Imamura, Takeshi ; Bever, Jennie ; Satoh, Hiroaki ; Lu, Juu Chin ; Hupfeld, Christopher J. ; Olefsky, Jerrold M. / 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. In: Molecular Endocrinology. 2005 ; Vol. 19, No. 11. pp. 2760-2768.
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AU - Bever, Jennie

AU - Satoh, Hiroaki

AU - Lu, Juu Chin

AU - Hupfeld, Christopher J.

AU - Olefsky, Jerrold M.

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