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.
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.
Authors: R M Quock; T H Burkey; E Varga; Y Hosohata; K Hosohata; S M Cowell; C A Slate; F J Ehlert; W R Roeske; H I Yamamura Journal: Pharmacol Rev Date: 1999-09 Impact factor: 25.468
Authors: Eric R Gross; Jason N Peart; Anna K Hsu; John A Auchampach; Garrett J Gross Journal: Am J Physiol Heart Circ Physiol Date: 2005-01-14 Impact factor: 4.733
Authors: M M Chou; W Hou; J Johnson; L K Graham; M H Lee; C S Chen; A C Newton; B S Schaffhausen; A Toker Journal: Curr Biol Date: 1998-09-24 Impact factor: 10.834