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Molecular Pharmacology

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Research ArticleArticle

Phosphorylation and Functional Desensitization of the α2A-Adrenergic Receptor by Protein Kinase C

Mei Liang, Margaret G. Eason, Elizabeth A. Jewell-Motz, Mark A. Williams, Cheryl T. Theiss, Gerald W. Dorn II and Stephen B. Liggett
Molecular Pharmacology July 1998, 54 (1) 44-49; DOI: https://doi.org/10.1124/mol.54.1.44
Mei Liang
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Margaret G. Eason
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Elizabeth A. Jewell-Motz
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Mark A. Williams
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Cheryl T. Theiss
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Gerald W. Dorn II
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Stephen B. Liggett
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Abstract

We have investigated the potential for protein kinase C (PKC) to phosphorylate and desensitize the α2A-adrenergic receptor (α2AAR). In whole-cell phosphorylation studies, recombinantly expressed human α2AAR displayed an increase in phosphorylation after short-term exposure to 100 nmphorbol 12-myristate-13-acetate (PMA) that was blocked by preincubation with a PKC inhibitor. This increase in receptor phosphorylation over basal amounted to 172 ± 40% in COS-7 cells and 201 ± 40% in Chinese hamster ovary cells. In permanently transfected Chinese hamster fibroblast cells, PKC activation by brief exposure of the cells to PMA resulted in a marked desensitization of α2AAR function, amounting to a 68 ± 4% decrease in the maximal agonist (UK14304)-stimulated intracellular calcium release. Such desensitization was blocked by the PKC inhibitor bisindolylmaleimide I and was not evoked by an inactive phorbol ester. The desensitization of this agonist response was not caused by PKC-mediated augmentation of G protein-coupled receptor kinase activity, because PMA-promoted desensitization of a mutated α2AAR that lacked G protein-coupled receptor kinase phosphorylation sites was identical to that of wild-type α2AAR. To test whether PKC phosphorylation is a mechanism by which α2AAR can be regulated by other receptors, the α1bAR was co-expressed with the α2AAR in Chinese hamster ovary cells. Upon selective activation of α1bAR, the function of α2AAR underwent a 53 ± 5% desensitization. Thus, cellular events that result in PKC activation promote phosphorylation of the α2AAR and lead to substantial desensitization of receptor function. This heterologous regulation also represents a mechanism by which rapid crosstalk between the α2AAR and other receptors can occur.

Footnotes

    • Received October 6, 1997.
    • Accepted March 30, 1998.
  • Send reprint requests to: Stephen Liggett, M.D., ML 0564, Room 7511, 231 Bethesda Avenue, Cincinnati, OH 45267-0564. E-mail:stephen.liggett{at}uc.edu

  • This work was supported by National Institutes of Health grants HL53436, HL41496, and HL49267.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Phosphorylation and Functional Desensitization of the α2A-Adrenergic Receptor by Protein Kinase C

Mei Liang, Margaret G. Eason, Elizabeth A. Jewell-Motz, Mark A. Williams, Cheryl T. Theiss, Gerald W. Dorn and Stephen B. Liggett
Molecular Pharmacology July 1, 1998, 54 (1) 44-49; DOI: https://doi.org/10.1124/mol.54.1.44

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Research ArticleArticle

Phosphorylation and Functional Desensitization of the α2A-Adrenergic Receptor by Protein Kinase C

Mei Liang, Margaret G. Eason, Elizabeth A. Jewell-Motz, Mark A. Williams, Cheryl T. Theiss, Gerald W. Dorn and Stephen B. Liggett
Molecular Pharmacology July 1, 1998, 54 (1) 44-49; DOI: https://doi.org/10.1124/mol.54.1.44
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