Premium
δ‐Opioid receptors stimulate GLUT1‐mediated glucose uptake through Src‐ and IGF‐1 receptor‐dependent activation of PI3‐kinase signalling in CHO cells
Author(s) -
Olianas Maria C,
Dedoni Simona,
Onali Pierluigi
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01234.x
Subject(s) - glucose transporter , wortmannin , glut1 , glut4 , glut3 , opioid receptor , protein kinase c , chemistry , proto oncogene tyrosine protein kinase src , endocrinology , medicine , protein kinase b , receptor , signal transduction , biology , microbiology and biotechnology , biochemistry , opioid , insulin
BACKGROUND AND PURPOSE Although opioids have been reported to affect glucose homeostasis, relatively little is known on the role of δ‐opioid receptors. We have investigated the regulation of glucose transport by human δ‐opioid receptors expressed in Chinese hamster ovary cells. EXPERIMENTAL APPROACH The uptake of [ 3 H]‐2‐deoxy‐D‐glucose and 3‐ O ‐[methyl‐[ 3 H]]‐D‐glucose in response to δ‐opioid receptor ligands and the expression of GLUT1, GLUT3 and GLUT4 glucose transporters were examined. Moreover, the effects of intracellular signal transduction inhibitors on δ‐opioid receptor‐regulated [ 3 H]‐2‐deoxy‐D‐glucose uptake and protein phosphorylation were investigated. KEY RESULTS Activation of δ‐opioid receptors rapidly stimulated [ 3 H]‐2‐deoxy‐D‐glucose and 3‐ O ‐[methyl‐[ 3 H]]‐D‐glucose uptakes, which were blocked by the GLUT inhibitors cytochalasin B and phloretin. The stimulation of [ 3 H]‐2‐deoxy‐D‐glucose uptake that occurred without a change in plasma membrane GLUT1 – required the coupling to G i /G o proteins – was independent of cAMP and extracellular signal‐regulated protein kinases, and was suppressed by blockade of Src and insulin‐like growth factor‐1 receptor (IGF‐1R) tyrosine kinases. Inhibition of phosphatidylinositol 3‐kinase (PI3K) by wortmannin or LY294002 and by PI3Kα, but not γ, isoform‐selective inhibitors greatly reduced the δ‐opioid receptor stimulation of glucose uptake. Moreover, the response was attenuated by overexpressing a dominant‐negative kinase‐deficient Akt form and by chemical inhibition of Akt. Stimulation of δ‐opioid receptors increased protein kinase Cζ/λ (PKCζ/λ) phosphorylation and a selective PKCζ/λ inhibitor slightly reduced opioid stimulation of glucose uptake. CONCLUSIONS AND IMPLICATIONS δ‐Opioid receptors stimulated glucose transport probably by enhancing GLUT1 intrinsic activity through a signalling cascade involving G i /G o , Src, IGF‐1R, PI3Kα, Akt and, to a minor extent, PKCζ/λ. This effect may contribute to the opioid regulation of glucose homeostasis in physio‐pathological conditions.