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Research ArticleCELLULAR AND MOLECULAR

Activation of Extracellular-Regulated Kinase by 5-Hydroxytryptamine2A Receptors in PC12 Cells is Protein Kinase C-Independent and Requires Calmodulin and Tyrosine Kinases

John C. Quinn, Nadine N. Johnson-Farley, JiYoung Yoon and Daniel S. Cowen
Journal of Pharmacology and Experimental Therapeutics November 2002, 303 (2) 746-752; DOI: https://doi.org/10.1124/jpet.102.038083
John C. Quinn
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Nadine N. Johnson-Farley
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JiYoung Yoon
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Daniel S. Cowen
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Abstract

5-Hydroxytryptamine (5-HT)2A receptors have been implicated to play a role in both the treatment and pathophysiology of a number of psychiatric disorders. Therefore, the coupling of this receptor to signals, such as extracellular signal-regulated kinase (ERK), that elicit long-term neuronal changes may be relevant. In the present study we examined the coupling of the Gq-coupled receptor to ERK in PC12 cells, a cell line commonly used as a neuronal model system. Activation of ERK occurred through a pathway different than the protein kinase C-dependent pathways described previously in studies of non-neuronal cells. Activation of ERK, in PC12 cells, was inhibited by both chelation of extracellular Ca2+ and by depletion of intracellular Ca2+ stores. Surprisingly, activation was not inhibited, but actually potentiated, by a variety of protein kinase C inhibitors covering all known protein kinase C isoforms. In contrast, the coupling of receptor to activation of ERK was found to be sensitive to N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W7) andN-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide (W13), inhibitors of calmodulin, but not to 1-(N,O-bis[5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl)-4-phenylpiperazine (KN62) and 2-[N-(2-hydroxyethyl)]-N-4-methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) (KN93), inhibitors of calmodulin-dependent protein kinase. Additionally, the general tyrosine kinase inhibitor genistein, as well as the Src inhibitor PP1 and the epidermal growth factor receptor kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG 1478), inhibited receptor-mediated activation of ERK, suggesting a role for tyrosine kinases. In fact, 5-HT was found to stimulate tyrosine phosphorylation of a number of proteins, and this phosphorylation was inhibited by W7. 5-HT2A receptor-activation of ERK through a protein kinase C-independent pathway requiring Ca2+/calmodulin/tyrosine kinases represents a pathway distinct from those described in studies of non-neuronal cells.

Footnotes

  • This study was supported by National Institute of Mental Health Grant MH60100 (to D.S.C).

  • DOI: 10.1124/jpet.102.038083

  • Abbreviations:
    5-HT
    5-hydroxytryptamine
    ERK
    extracellular signal-regulated kinase
    PKC
    protein kinase C
    H89
    N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide
    PI
    phosphoinositide
    phorbol 12-myristate-13-acetate
    CaM, calmodulin
    PKA
    protein kinase A
    EGF
    epidermal growth factor
    AG 17
    tyrphostin A9
    W7
    N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride
    W13
    N-(4-aminobutyl)-5-chloro-1-naphthalenesulfonamide
    AG 1478
    4-(3-chloroanilino)-6,7-dimethoxyquinazoline
    KN62
    1-(N,O-bis[5-isoquinolinesulfonyl]-N-methyl-l-tyrosyl)-4-phenylpiperazine
    KN93
    2-[N-(2-hydroxyethyl)]-N-(4-methyoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine)
    MDL 100907
    R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol
    Go6983
    2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide
    Go6976
    12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole
    Ro-31-8220
    3-[1-[3-amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide
    PP1
    {4-amino-1-tert-butyl-3-(1′-naphthyl)pyrazolo[3,4-d]pyrimidine}
    SB206553
    N-3-pyridinyl-3,5-dihydro-5-methylbenzo(1,2-b:4,5-b′)dipyrrole-1(2H)carboxamide
    LY-278,584
    1-methyl-N-(8-methyl-8-azabicyclo[3.2.1]-oct-3-yl)-1H-indazole-3-carboxamide
    • Received April 26, 2002.
    • Accepted August 8, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 2
1 Nov 2002
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Research ArticleCELLULAR AND MOLECULAR

Activation of Extracellular-Regulated Kinase by 5-Hydroxytryptamine2A Receptors in PC12 Cells is Protein Kinase C-Independent and Requires Calmodulin and Tyrosine Kinases

John C. Quinn, Nadine N. Johnson-Farley, JiYoung Yoon and Daniel S. Cowen
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 746-752; DOI: https://doi.org/10.1124/jpet.102.038083

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Research ArticleCELLULAR AND MOLECULAR

Activation of Extracellular-Regulated Kinase by 5-Hydroxytryptamine2A Receptors in PC12 Cells is Protein Kinase C-Independent and Requires Calmodulin and Tyrosine Kinases

John C. Quinn, Nadine N. Johnson-Farley, JiYoung Yoon and Daniel S. Cowen
Journal of Pharmacology and Experimental Therapeutics November 1, 2002, 303 (2) 746-752; DOI: https://doi.org/10.1124/jpet.102.038083
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