?-Opioid receptors stimulate GLUT1-mediated glucose uptake through Src- and IGF-1 receptor-dependent activation of PI3-kinase signalling in CHO cells.

ABSTRACT:

Background and purpose

Although opioids have been reported to affect glucose homeostasis, relatively little is known on the role of ?-opioid receptors. We have investigated the regulation of glucose transport by human ?-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 ?-opioid receptor ligands and the expression of GLUT1, GLUT3 and GLUT4 glucose transporters were examined. Moreover, the effects of intracellular signal transduction inhibitors on ?-opioid receptor-regulated [(3)H]-2-deoxy-D-glucose uptake and protein phosphorylation were investigated.

Key results

Activation of ?-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 PI3K?, but not ?, isoform-selective inhibitors greatly reduced the ?-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 ?-opioid receptors increased protein kinase C?/? (PKC?/?) phosphorylation and a selective PKC?/? inhibitor slightly reduced opioid stimulation of glucose uptake.

Conclusions and implications

?-Opioid receptors stimulated glucose transport probably by enhancing GLUT1 intrinsic activity through a signalling cascade involving G(i)/G(o), Src, IGF-1R, PI3K?, Akt and, to a minor extent, PKC?/?. This effect may contribute to the opioid regulation of glucose homeostasis in physio-pathological conditions.

SUBMITTER: Olianas MC 

PROVIDER: S-EPMC3101623 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature