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Molecular Pharmacology

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Research ArticleArticle

Signaling Pathways Leading to Phosphorylation of Akt and GSK-3β by Activation of Cloned Human and Rat Cerebral D2 and D3 Receptors

Clotilde Mannoury la Cour, Marie-Josèphe Salles, Valérie Pasteau and Mark J. Millan
Molecular Pharmacology January 2011, 79 (1) 91-105; DOI: https://doi.org/10.1124/mol.110.065409
Clotilde Mannoury la Cour
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Marie-Josèphe Salles
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Valérie Pasteau
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Mark J. Millan
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Abstract

Although dopamine (DA) regulates the serine/threonine kinase Akt and its downstream substrate glycogen synthase kinase-3β (GSK-3β), the direct influence of dopaminergic receptors remains poorly characterized. Short-term incubation of Chinese hamster ovary (CHO)-expressed human (h)D2L and hD3 receptors with DA (maximal effect, 5–10 min) phosphorylated Akt (Thr308 and Ser473) and GSK-3β (Ser9), actions blocked by the selective D2 and D3 antagonists, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) and (3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide (S33084), respectively. Similar findings were acquired with the specific D2/D3 receptor agonist quinelorane, which also enhanced (10 min after administration) levels of p-Akt and p-GSK-3β in rat nucleus accumbens, an action blocked by the D2/D3 receptor antagonist raclopride. Akt and GSK-3β phosphorylation mediated via CHO-expressed hD2L and hD3 receptors was prevented by pertussis toxin and by inhibitors of insulin-like growth factor-1 receptors as well as phosphatidylinositol 3-kinase and Src. Likewise, chelation of intracellular Ca2+ and interference with an “atypical” phorbol ester-insensitive protein kinase C (PKC) abolished recruitment of Akt and GSK-3β. Inactivation of PKCμ blocked Akt and GSK-3β phosphorylation at hD2L receptors. However, blockade of conventional PKC isoforms attenuated the actions of DA at hD3 receptors only. Furthermore, phospholipase C (PLC), calmodulin, and Akt inhibitors abolished DA-induced GSK-3β phosphorylation by hD3 receptors, whereas phosphorylation by hD2L receptors partially involved calmodulin, Akt, and extracellular signal-regulated kinase (ERK) 1/2. In conclusion, at both hD2L and hD3 receptors, DA elicited a Gi/o- and Ca2+/calmodulin-dependent phosphorylation of Akt and GSK-3β via transactivation of insulin-like growth factor 1 receptor. However, significant differences were seen regarding the involvement of PLC, calmodulin, and ERK1/2.

Footnotes

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

    doi:10.1124/mol.110.065409.

  • ABBREVIATIONS:

    10-DEBC
    10-[4′-(N,N-diethylamino)butyl]-2-chlorophenoxazine
    AG1024
    3-bromo-5-t-butyl-4-hydroxy-benzildenemalonitrile
    AG1433
    2-(3,4-dihydroxyphenyl)-6,7-dimethoxyquinoxaline
    AG1478
    4-(3-chloroanilino)-6,7-dimethoxyquinazoline
    BAPTA-AM
    1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl)ester
    CaMKII
    Ca2+-calmodulin kinase
    CHO
    Chinese hamster ovary
    CTX
    cholera toxin
    DA
    dopamine
    EGF
    epidermal growth factor
    EGF-R
    epidermal growth factor receptor
    ERK1/2
    extracellular signal-regulated kinase
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    Gö6976
    12-(2-cyanoethyl)-6,7,12,13,-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazol
    Gö6983
    3-[1(3-dimethylamino-propyl)-5-methoxy-1H-indol-3-yl]4-(1H-indol-3-yl)pyrrolidine-2,5-dione
    GSK-3β
    glycogen synthase kinase-3β
    h
    human
    H89
    N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide
    IGF
    insulin-like growth factor
    IGF-1R
    insulin-like growth factor-1 receptor
    KN93
    2-(N-[2-hydroxyethyl])-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylamine
    L741
    6263-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole
    LY294,002
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopiran-4-one
    MAPK
    mitogen-activated protein kinase
    MEK
    MAPK-extracellular signal-regulated kinase
    mTORC
    rictor-mammalian target of rapamycin complex
    PAO
    phenylarsine oxide
    PD98059
    2′-amino-3′-methoxyflavone
    PDGF
    platelet-derived growth factor
    PDGF-R
    platelet-derived growth factor receptor
    PDK1
    phosphatidylinositol 3,4,5-trisphosphate-dependent protein kinase 1
    PI3-K
    phosphatidyl inositol-3-kinase
    PKA
    protein kinase A
    PKC
    protein kinase C
    PLC
    phospholipase C
    PMA
    phorbol 12-myristate 13-acetate
    PP2
    4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine
    PTX
    pertussis toxin
    Ro-31-7549
    2-[1-3(aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl-maleimide, acetate
    S33084
    (3aR,9bS)-N[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl] (4-phenyl)benzamide)
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene
    U73122
    1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione
    W7
    N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide
    Wnt
    Wingless.

  • Received April 7, 2010.
  • Accepted October 14, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (1)
Molecular Pharmacology
Vol. 79, Issue 1
1 Jan 2011
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Research ArticleArticle

Signaling Pathways Leading to Phosphorylation of Akt and GSK-3β by Activation of Cloned Human and Rat Cerebral D2 and D3 Receptors

Clotilde Mannoury la Cour, Marie-Josèphe Salles, Valérie Pasteau and Mark J. Millan
Molecular Pharmacology January 1, 2011, 79 (1) 91-105; DOI: https://doi.org/10.1124/mol.110.065409

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Research ArticleArticle

Signaling Pathways Leading to Phosphorylation of Akt and GSK-3β by Activation of Cloned Human and Rat Cerebral D2 and D3 Receptors

Clotilde Mannoury la Cour, Marie-Josèphe Salles, Valérie Pasteau and Mark J. Millan
Molecular Pharmacology January 1, 2011, 79 (1) 91-105; DOI: https://doi.org/10.1124/mol.110.065409
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