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Volume 270, Number 18, Issue of May 5, pp. 10952-10959, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Long Term Phorbol Ester Treatment Down-regulates the -Adrenergic Receptor in 3T3-F442A Adipocytes

Bruno Fève , France Piétri-Rouxel , Khadija El Hadri , Marie-Franoise Drumare , A. Donny Strosberg

The role of protein kinase C (PKC) in the regulation of the -adrenergic receptor (-AR) gene was examined in murine 3T3-F442A adipocytes, which express this receptor subtype at a high level. We also investigated the involvement of this kinase in the modulation of -AR gene expression by insulin. Long term exposure of 3T3-F442A adipocytes to phorbol 12-myristate 13-acetate (PMA) decreased -AR mRNA content in a time- and concentration-dependent manner, with maximal changes observed at 6 h (6.5-fold decrease) and at 100 nM PMA. This inhibition was selective for -AR transcripts, since - and -AR mRNA content remained unchanged. Also, (-)-[I]cyanopindolol saturation and competition binding experiments on adipocyte membranes indicated that PMA induced an 2-fold decrease in -AR expression, while that of the two other subtypes was not affected. This correlated with a lower efficacy of -AR agonists to stimulate adenylyl cyclase. Conversely, long term exposure to PMA did not alter adenylyl cyclase activity in response to guanosine 5`- O-(3-thiotriphosphate) or forskolin. The inactive phorbol ester 4-phorbol 12,13-didecanoate did not repress -AR mRNA levels. Inhibition of -AR mRNA by PMA was suppressed by the PKC-selective inhibitor bisindolylmaleimide, and was not observed in PKC-depleted cells, indicating that PKC was involved in this response. mRNA turnover experiments showed that the half-life of -AR transcripts was not affected by long term PMA exposure. When 3T3-F442A adipocytes were pretreated with PMA for 24 h to down-regulate PKC, or with bisindolylmaleimide, the insulin-induced inhibition of -AR mRNA levels was reduced by 44-67%. These findings demonstrate that sustained PKC activation exerts a specific control of -AR gene expression and is involved, at least in part, in the modulation by insulin of this adrenergic receptor subtype.

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