Alpha2-Adrenergic Agonist Brimonidine Stimulates ERK1/2 and AKT Signaling Via Transactivation of EGF Receptors in MIO-M1 Human Müller Cells
(English)Manuscript (preprint) (Other academic)
Alpha2-adrenergic receptor (α2-ADR) agonist brimonidine is clinically used in glaucoma and ocular hypertension treatment and has been shown to protect the retina from adverse effects. The purpose of this study to test the hypothesis that brimonidine stimulates extracellular signal-regulated kinases (ERK) 1/2 and AKT signaling via transactivation of epidermal growth factor receptors in MIO-M1 human Müller cells. MIO-M1 cells were treated with brimonidine in combination with Src-kinase, epidermal growth factor receptor kinase, and matrix metalloproteinase inhibitors and analyzed by immunocytochemistry, quantitative PCR and western blot techniques. Our results show that human MIO-M1 cells express α2A-ADR and stimulation of that by brimonidine caused a robust increase of ERK1/2 and AKT (Thr-308) phosphorylation in MIO-M1 cells. The P-ERK1/2 and P-AKT (Thr-308) signaling were mediated by Src-kinase, associated with phosphorylation of tyrosine residue of epidermal growth factor receptor (P-EGFR Y1173) and activation of matrix metalloproteinase. These effects could be blocked by Src-kinase inhibitors (PP1, PP2), EGFR-kinase inhibitor (AG1478) and matrix metalloproteinases inhibitor (GM6001). These results conclude that human MIO-M1 cells express α2A-ADR and brimonidine triggers Srckinase mediated both ligand-dependent and ligand-independent EGFR transactivation. Transactivation leads to activation of ERK1/2 and AKT signaling in MIO-M1 human Müller cells.
AKT pathway, Alpha 2-adrenergic receptors, Brimonidine, EGF receptor, ERK1/2, Matrix metalloproteinases, MIO-M1 human Müller cell, and Src-kinase
Research subject Medical Science
IdentifiersURN: urn:nbn:se:uu:diva-281576OAI: oai:DiVA.org:uu-281576DiVA: diva2:914631