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Research ArticleCELLULAR AND MOLECULAR

Tonic Inhibitory Role for cAMP in α1a-Adrenergic Receptor Coupling to Extracellular Signal-Regulated Kinases 1/2

Xiuxiang Jiao, Pedro J. Gonzalez-Cabrera, Lei Xiao, Michael E. Bradley, Peter W. Abel and William B. Jeffries
Journal of Pharmacology and Experimental Therapeutics October 2002, 303 (1) 247-256; DOI: https://doi.org/10.1124/jpet.102.037747
Xiuxiang Jiao
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Pedro J. Gonzalez-Cabrera
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Lei Xiao
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Michael E. Bradley
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Peter W. Abel
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William B. Jeffries
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Abstract

α1a-Adrenergic receptors (ARs) couple to phosphoinositide hydrolysis, adenylyl cyclase, and mitogen-activated protein kinase (MAPK) pathways. However, the interaction among these signaling pathways in activating extracellular signal-regulated kinase 1/2 (ERK1/2) is not well understood. We investigated the coupling of α1a-ARs to ERK1/2 in Chinese hamster ovary (CHO)-K1 cells stably transfected with mouse α1a-ARs, as well as the interaction between ERK1/2 and norepinephrine-induced cAMP accumulation. α1a-AR activation by norepinephrine increased the cytosolic Ca2+ concentration and phosphorylated ERK1/2 in a time- and concentration-dependent manner. ERK1/2 phosphorylation was blocked by the MAPK kinase 1/2 inhibitor 2′-amino-3′-methoxyflavone (PD 98059) and the α1-AR antagonist prazosin. A transient elevation in intracellular Ca2+ was required for the phosphorylation of ERK1/2; however, activation of protein kinase C did not seem to be required for ERK1/2 phosphorylation. Norepinephrine also stimulated cAMP accumulation in transfected CHO-K1 cells in a concentration-dependent manner via α1a-ARs, which was blocked by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid. Norepinephrine-induced ERK1/2 phosphorylation was inhibited by the adenylyl cyclase activator forskolin and was enhanced by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ 22536) and the protein kinase A inhibitor 4-cyano-3-methylisoquinoline. In conclusion, in transfected CHO-K1 cells, α1a-AR activation activates both phospholipase C and adenylyl cyclase-mediated signaling pathways. α1a-AR-mediated ERK1/2 phosphorylation was dependent on a rise in intracellular Ca2+, and this pathway was reciprocally regulated by the concomitant activation of adenylyl cyclase, which inhibits ERK1/2 phosphorylation. Thus, α1a-AR stimulation of cAMP production may play an important role in regulating ERK1/2 phosphorylation in cell lines and native tissues.

Footnotes

  • ↵1 Current address: Department of Cardiovascular Biology, Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195.

  • ↵2 Current address: Myocardial Biology Unit, Cardiovascular Division, Department of Medicine, Boston University School of Medicine, Boston, MA 02118.

  • This work was supported by Grant 9607830S from the American Heart Association (to W.B.J.) and Grant HD 33430 from National Institutes of Health (to M.E.B.).

  • DOI: 10.1124/jpet.102.037747

  • Abbreviations:
    AR
    adrenergic receptor
    PLC
    phospholipase C
    MAPK
    mitogen-activated protein kinase
    IP3
    inositol 1,4,5-trisphosphate
    DAG
    diacylglycerol
    PKC
    protein kinase C
    ERK
    extracellular signal-regulated kinase
    MEK
    mitogen-activated protein kinase kinase
    PKA
    protein kinase A
    CHO
    Chinese hamster ovary
    PMA
    phorbol 12-myristate 13-acetate
    BAPTA
    1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
    CMQ
    4-cyano-3-methylisoquinoline
    AM
    acetoxymethyl ester
    PD 98059
    2′-amino-3′-methoxyflavone
    BMY-7378
    8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione
    SQ 22536
    9-(tetrahydro-2-furanyl)-9H-purine-6-amine
    • Received April 18, 2002.
    • Accepted June 17, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 303 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 303, Issue 1
1 Oct 2002
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Research ArticleCELLULAR AND MOLECULAR

Tonic Inhibitory Role for cAMP in α1a-Adrenergic Receptor Coupling to Extracellular Signal-Regulated Kinases 1/2

Xiuxiang Jiao, Pedro J. Gonzalez-Cabrera, Lei Xiao, Michael E. Bradley, Peter W. Abel and William B. Jeffries
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 247-256; DOI: https://doi.org/10.1124/jpet.102.037747

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Research ArticleCELLULAR AND MOLECULAR

Tonic Inhibitory Role for cAMP in α1a-Adrenergic Receptor Coupling to Extracellular Signal-Regulated Kinases 1/2

Xiuxiang Jiao, Pedro J. Gonzalez-Cabrera, Lei Xiao, Michael E. Bradley, Peter W. Abel and William B. Jeffries
Journal of Pharmacology and Experimental Therapeutics October 1, 2002, 303 (1) 247-256; DOI: https://doi.org/10.1124/jpet.102.037747
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