Adenosine A(1) receptor-mediated transactivation of the EGF receptor produces a neuroprotective effect on cortical neurons in vitro.
OBJECTIVE
To understand the mechanism of the transactivation of the epidermal growth factor receptor (EGFR) mediated by the adenosine A(1) receptor (A(1)R).


METHODS
Primary cultured rat cortical neurons subjected to oxygen-glucose deprivation (OGD) and HEK293/A(1)R cells were treated with the A(1)R-specific agonist N(6)-cyclopentyladenosine (CPA). Phospho-EGFR, Akt, and ERK1/2 were observed by Western blot. An interaction between EGFR and A(1)R was detected using immunoprecipitation and immunocytochemistry.


RESULTS
The A(1)R agonist CPA causes protein kinase B (Akt) activation and protects primary cortical neurons from oxygen-glucose deprivation (OGD) insult. A(1)R and EGFR co-localize in the membranes of neurons and form an immunocomplex. A(1)R 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/A(1)R cells. The response to the A(1)R agonist is mediated primarily through EGFR transactivation that is dependent on pertussis toxin (PTX)-sensitive G(i) protein and metalloproteases in HEK 293/A(1)R.


CONCLUSIONS
A(1)R-mediated EGFR transactivation confers a neuroprotective effect in primary cortical neurons. PI3 kinase and Src kinase play pivotal roles in this response.Acta Pharmacologica Sinica (2009) 30: 889-898; doi: 10.1038/aps.2009.80.
Xie
Ke-Qiang
KQ
State Key Laboratory of Drug Research, Department of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Zhang
Li-Min
LM
Cao
Yan
Y
Zhu
Jun
J
Feng
Lin-Yin
LY
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D018696:Neuroprotective Agents; D043682:Receptor, Adenosine A1; C048599:N(6)-cyclopentyladenosine; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000241:Adenosine