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Research ArticleArticle

δ-Opioid Receptors Stimulate the Metabolic Sensor AMP-Activated Protein Kinase through Coincident Signaling with Gq/11-Coupled Receptors

Maria C. Olianas, Simona Dedoni, Alessandra Olianas and Pierluigi Onali
Molecular Pharmacology February 2012, 81 (2) 154-165; DOI: https://doi.org/10.1124/mol.111.075267
Maria C. Olianas
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Simona Dedoni
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Alessandra Olianas
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Pierluigi Onali
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Abstract

AMP-activated protein kinase (AMPK) and δ-opioid receptors (DORs) are both involved in controlling cell survival, energy metabolism, and food intake, but little is known on the interaction between these two signaling molecules. Here we show that activation of human DORs stably expressed in Chinese hamster ovary (CHO) cells increased AMPK activity and AMPK phosphorylation on Thr172. DOR-induced AMPK phosphorylation was prevented by pertussis toxin, reduced by protein kinase A (PKA) activators, and unaffected by PKA, transforming growth factor-β-activated kinase 1, mitogen-activated protein kinase, and protein kinase C inhibitors. Conversely, the DOR effect was reduced by Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) inhibition, apyrase treatment, Gq/11 antagonism, and blockade of P2 purinergic receptors. Apyrase treatment also depressed DOR stimulation of intracellular Ca2+ concentration, whereas P2 receptor antagonism blocked DOR stimulation of inositol phosphate accumulation. In SH-SY5Y neuroblastoma cells and primary olfactory bulb neurons, DOR activation failed to affect AMPK phosphorylation per se but potentiated the stimulation by either muscarinic agonists or 2-methyl-thio-ADP. Sequestration of G protein βγ subunits (Gβγ) blocked the DOR potentiation of AMPK phosphorylation induced by oxotremorine-M. In CHO cells, the AMPK activator 5-aminoimidazole-4-carboxamide1-β-d-ribonucleoside stimulated AMPK phosphorylation and glucose uptake, whereas pharmacological inhibition of AMPK, expression of a dominant-negative mutant of AMPKα1, and P2Y receptor blockade reduced DOR-stimulated glucose uptake. The data indicate that in different cell systems, DOR activation up-regulates AMPK through a Gβγ-dependent synergistic interaction with Gq/11-coupled receptors, potentiating Ca2+ release and CaMKKβ-dependent AMPK phosphorylation. In CHO cells, this coincident signaling mechanism is involved in DOR-induced glucose uptake.

Footnotes

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.075267.

  • ABBREVIATIONS:

    ACC
    acetyl-coenzyme A carboxylase
    ADV
    adenovirus
    AICAR
    5-aminoimidazole-4-carboxamide1-β-d-ribonucleoside
    AMPK
    AMP-activated protein kinase
    ANOVA
    analysis of variance
    BSA
    bovine serum albumin
    CaMKK
    Ca2+/calmodulin-dependent protein kinase kinase
    CCh
    carbachol
    CHO
    Chinese hamster ovary
    CHO/DOR
    CHO cells stably expressing human DOR
    compound C
    6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine
    dBcAMP
    dibutyryl-cAMP
    DN
    dominant-negative
    DOR
    δ-opioid receptors
    DPDPE
    [d-Pen(2,5)]-enkephalin
    DTT
    dithiothreitol
    FCS
    fetal calf serum
    GLUT
    glucose transporter
    Go 6983
    3-[1-[3-(dimethylamino)propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
    GRK2-CT
    C-terminal region of G protein-coupled receptor kinase 2
    HPLC
    high-performance liquid chromatography
    IGF-1
    insulin-like growth factor-1
    IP
    inositol phosphate
    LDH
    lactate dehydrogenase
    MAP
    mitogen-activated protein
    MeSADP
    2-methylthio ADP
    MRS 2179
    N6-methyl 2′-deoxyadenosine 3′,5′-bisphosphate
    naltrindole
    17-(cyclopropylmethyl)-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-6,7–2′,3′-indolomorphinan
    NTI
    naltrindole
    Oxo-M
    oxotremorine-M
    PBS
    phosphate-buffered saline
    PD 98059
    2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
    PI3K
    phosphatidylinositol 3-kinase
    PKA
    protein kinase A
    PKC
    protein kinase C
    PLC
    phospholipase C
    PPADS
    pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid
    PTX
    Bordetella pertussis toxin
    Rp-cAMPS
    adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer
    SB203580
    4-[5-(4-fluorophenyl)-2-[4-(methylsulphonyl)phenyl]-1H-imidazol-4-yl]pyridine
    SAMS peptide
    HMRSAMSGLHLVKRR
    SNC 80
    (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
    SP600125
    anthra[1–9-cd]pyrazol-6(2H)-one
    Sp-cAMPS
    adenosine-3′,5′-cyclic monophosphorothioate, Sp-isomer
    STO-609
    7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid
    TAK1
    transforming growth factor-β-activated kinase 1.

  • Received August 11, 2011.
  • Accepted October 26, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (2)
Molecular Pharmacology
Vol. 81, Issue 2
1 Feb 2012
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Research ArticleArticle

AMPK Activation by δ-Opioid Receptors

Maria C. Olianas, Simona Dedoni, Alessandra Olianas and Pierluigi Onali
Molecular Pharmacology February 1, 2012, 81 (2) 154-165; DOI: https://doi.org/10.1124/mol.111.075267

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Research ArticleArticle

AMPK Activation by δ-Opioid Receptors

Maria C. Olianas, Simona Dedoni, Alessandra Olianas and Pierluigi Onali
Molecular Pharmacology February 1, 2012, 81 (2) 154-165; DOI: https://doi.org/10.1124/mol.111.075267
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