Protein kinase C-mediated down-regulation of β1-adrenergic receptor gene expression in rat C6 glioma cells

Zhongwei Li, Vidita A. Vaidya, John D. Alvaro, Philip A. Iredale, Richard Hsu, Ginger Hoffman, Laura Fitzgerald, Patricia K. Curran, Curtis A. Machida, Peter H. Fishman, Ronald S. Duman

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17 Scopus citations

Abstract

In the current study, we investigated the, mechanism by which protein kinase C (PKC) regulates the expression of β1-adrenergic receptor (β1AR) mRNA in rat C6 glioma cells. Exposure of the cells to 4β-phorbol-12- myristate-13-acetate (PMA), an activator PKC, resulted in a down-regulation of both β1AR binding sites and mRNA levels in a time- and concentration- dependent manner. This effect was not observed with phorbol esters that do not activate PKC and was blocked by bisindolylmaleimide, a specific PKC inhibitor. Activation of PKC did not reduce the half-life of β1AR mRNA but significantly decreased the activity of the β1AR promoter, as determined by reporter analysis. A putative response element, with partial homology to a consensus cAMP response element, was identified by mutation analysis of the promoter at positions -343 to -336, relative to the translational start site. Mutation of this putative regulatory element, referred to as a β1AR-PKC response element, completely blocked the PKC-mediated down-regulation of β1AR promoter activity. Gel mobility shift analysis detected two specific bands when C6 cell extracts were incubated with a labeled DNA probe containing the β1AR-PKC response element sequence. Formation of one of these bands was inhibited by an oligonucleotide probe containing a consensus CRE and disrupted by an antibody for cAMP response element binding protein. Based on these studies, we propose that the PKC-induced down-regulation of β1AR gene transcription in C6 cells is mediated in part by a cAMP response element binding protein-dependent mechanism acting on a novel response element.

Original languageEnglish (US)
Pages (from-to)14-21
Number of pages8
JournalMolecular pharmacology
Volume54
Issue number1
DOIs
StatePublished - Jul 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Li, Z., Vaidya, V. A., Alvaro, J. D., Iredale, P. A., Hsu, R., Hoffman, G., Fitzgerald, L., Curran, P. K., Machida, C. A., Fishman, P. H., & Duman, R. S. (1998). Protein kinase C-mediated down-regulation of β1-adrenergic receptor gene expression in rat C6 glioma cells. Molecular pharmacology, 54(1), 14-21. https://doi.org/10.1124/mol.54.1.14