α2B-Adrenergic Receptor Activates MAPK via a Pathway Involving Arachidonic Acid Metabolism, Matrix Metalloproteinases, and Epidermal Growth Factor Receptor Transactivation

• Published in: The Journal of biological chemistry 2002-05, Vol.277 (22), p.19882-19888
• Main Authors: Cussac, Daniel, Schaak, Stéphane, Denis, Colette, Paris, Hervé
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110142200

We have investigated the mechanisms whereby α2B-adrenergic receptor (α2B-AR) promotes MAPK activation in a clone of the renal tubular cell line, LLC-PK1, transfected with the rat nonglycosylated α2-AR gene. Treatment of LLC-PK1-α2Bwith UK14304 or dexmedetomidine caused arachidonic acid (AA) release and ERK2 phosphorylation. AA release was abolished by prior treatment of the cells with pertussis toxin, quinacrine, or methyl arachidonyl fluorophosphonate but not by the addition of the MEK inhibitor U0126. The effects of α2-agonists on MAPK phosphorylation were mimicked by cell exposure to exogenous AA. On the other hand, quinacrine abolished the effects of UK14304, but not of AA, suggesting that AA released through PLA2 is responsible for MAPK activation by α2B-AR. The effects of α2-agonists or AA were PKC-independent and were attenuated by indomethacin and nordihydroguaiaretic acid. Treatment with batimastat, CRM 197, or tyrphostin AG1478 suppressed MAPK phosphorylation promoted by α2-agonist or AA. Furthermore, conditioned culture medium from UK14304-treated LLC-PK1-α2B induced MAPK phosphorylation in wild-type LLC-PK1. Based on these data, we propose a model whereby activation of MAPK by α2B-AR is mediated through stimulation of PLA2, AA release, generation of AA derivatives, activation of matrix metalloproteinases, release of heparin-binding EGF-like growth factor, transactivation of epidermal growth factor receptor, and recruitment of Shc. Whether this pathway is particular to α2B-AR and LLC-PK1 or whether it can be extended to other cell types and/or other G-protein-coupled receptors remains to be established.