Acta Pharmacologica Sinica (2009) 30: 889-898; doi: 10.1038/aps.2009.80

Aim: To understand the mechanism of the transactivation of the epidermal growth factor receptor (EGFR) mediated by the adenosine A₁ receptor (A₁R). 

Methods: Primary cultured rat cortical neurons subjected to oxygen-glucose deprivation (OGD) and HEK293/A₁R cells were treated with the A₁R-specific agonist N⁶-cyclopentyladenosine (CPA).  Phospho-EGFR, Akt, and ERK1/2 were observed by Western blot.  An interaction between EGFR and A₁R was detected using immunoprecipitation and immunocytochemistry.   

Results: The A₁R agonist CPA causes protein kinase B (Akt) activation and protects primary cortical neurons from oxygen-glucose deprivation (OGD) insult.  A₁R and EGFR co-localize in the membranes of neurons and form an immunocomplex.  A₁R stimulation induces significant EGFR phosphorylation via a PI3K and Src kinase signaling pathway; this stimulation provides a neuroprotective effect in cortical neurons.  CPA leads to sustained phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) in cortical neurons, but only to transient phosphorylation in HEK 293/A₁R cells.  The response to the A₁R agonist is mediated primarily through EGFR transactivation that is dependent on pertussis toxin (PTX)-sensitive G_i protein and metalloproteases in HEK 293/A₁R. 

Conclusion: A₁R-mediated EGFR transactivation confers a neuroprotective effect in primary cortical neurons.  PI3 kinase and Src kinase play pivotal roles in this response.

Keywords: adenosine A₁ receptor; epidermal growth factor receptor; transactivation; Akt; Src kinase; ERK1/2; G_i protein; metalloprotease; PI3K