Abstract
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 Gi 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.
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Acknowledgements
The authors thank Mr Lei JIN and Miss Li HUANG for help with analyzing the data. This work was supported by research grants from the National Basic Research Program of China (973 Program) 2007CB935804.
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Xie, Kq., Zhang, Lm., Cao, Y. et al. Adenosine A1 receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro. Acta Pharmacol Sin 30, 889–898 (2009). https://doi.org/10.1038/aps.2009.80
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DOI: https://doi.org/10.1038/aps.2009.80
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