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alpha 2B-adrenergic receptor activates MAPK via a pathway involving arachidonic acid metabolism, matrix metalloproteinases, and epidermal growth factor receptor transactivation.

Authors: Cussac, D  Schaak, S  Denis, C  Paris, H 
Citation: Cussac D, etal., J Biol Chem 2002 May 31;277(22):19882-8. Epub 2002 Mar 12.
Pubmed: (View Article at PubMed) PMID:11891218
DOI: Full-text: DOI:10.1074/jbc.M110142200

We have investigated the mechanisms whereby alpha(2B)-adrenergic receptor (alpha(2B)-AR) promotes MAPK activation in a clone of the renal tubular cell line, LLC-PK1, transfected with the rat nonglycosylated alpha(2)-AR gene. Treatment of LLC-PK1-alpha(2B) with 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 alpha(2)-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 alpha(2B)-AR. The effects of alpha(2)-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 alpha(2)-agonist or AA. Furthermore, conditioned culture medium from UK14304-treated LLC-PK1-alpha(2B) induced MAPK phosphorylation in wild-type LLC-PK1. Based on these data, we propose a model whereby activation of MAPK by alpha(2B)-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 alpha(2B)-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.


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CRRD Object Information
CRRD ID: 1304238
Created: 2004-12-22
Species: All species
Last Modified: 2004-12-22
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.