Transactivation of EGF receptors in chicken Müller cells by α2A-adrenergic receptors stimulated by brimonidine.
OBJECTIVE
Alpha2-adrenergic receptor agonists are used in glaucoma treatment and have been shown to have some neuroprotective effects. We performed this study to test the hypothesis that epidermal growth factor receptors on chicken Müller cells are transactivated by α2-adrenergic receptors and we focused on the extracellular signal-activated kinases 1/2 (ERK) pathway.


METHODS
Embryonic chicken retina and cultures of primary Müller cells were stimulated by α2-adrenergic receptor agonist brimonidine. Immunostaining, quantitative RT-PCR, and Western blot techniques, in combination with Src, epidermal growth factor receptor kinase, and matrix metalloproteinase inhibitors, were used for analysis of the cellular responses.


RESULTS
Our results showed that Müller cells express α2A-adrenergic receptors in vivo and in vitro and that brimonidine triggered a robust and transient phosphorylation of ERK1/2. This ERK-response was Src-kinase dependent, associated with tyrosine phosphorylation of epidermal growth factor receptors (phospho-Y1068, Y1173) and was mediated by matrix metalloproteinase activity on the Müller cells.


CONCLUSIONS
Müller cells express the α2A-adrenergic receptor, and brimonidine triggers both Src-kinase- and matrix metalloproteinase-mediated autocrine ligand-dependent activation of epidermal growth factor receptors on Müller cells. This response is consistent with transactivation of epidermal growth factor receptors by stimulation of α2-adrenergic receptors.
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Mohammad
M
Harun-Or-Rashid
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Niclas
N
Lindqvist
Department of Neuroscience, Uppsala University, Uppsala, Sweden.
Finn
F
Hallböök
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D000068438:Brimonidine Tartrate; D002478:Cells, Cultured; D002642:Chick Embryo; D063928:Ependymoglial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D005901:Glaucoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology*; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation
D058647:Adrenergic alpha-2 Receptor Agonists; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D012313:RNA; D066246:ErbB Receptors
EGF receptor; Müller cells; alpha2-adrenergic agonists; metalloproteinases; transactivation