The Endothelin B Receptor Transactivates Epidermal Growth Factor Receptors in primary chicken Müller cells and in MIO-M1 Human Müller Cells
(English)Manuscript (preprint) (Other academic)
Injury to the nervous system elicits signals that trigger a variety of cellular responses. Injury to the retina triggers Müller cells, the major glia cell of the retina, to dedifferentiate, proliferate, attain retinal progenitor properties and in some species generate new neurons. The epidermal growth factor receptor (EGFR) system and extracellular signal-regulated kinase (ERK) signalling are key regulators of these processes in Müller cells. The complexity of the extracellular signals that modulate and control the process are not fully understood. In this work we studied whether endothelin receptor signalling can activate EGFR and ERK signalling in Müller cells. Endothelin expression is robustly up-regulated at retinal injury and endothelin receptors have been shown to transactivate EGFRs in other cell-types. We treated chicken Müller cells in vivo, cultured primary chicken Müller cells and the human Müller cell line MIO-M1 with receptor agonists and enzyme blockers, and analyzed endothelin receptor mediated transactivation of EGFRs by using western blot analysis, quantitative reverse transcriptase PCR and immunocytochemistry. The results showed that both chicken and human Müller cells express endothelin receptor B. Stimulation by using the endothelin receptor B agonist IRL1620 caused Src-kinase mediated ligand-dependent and ligand-independent EGFR transactivation. The effects could be blocked by Src-kinase inhibitors (PP1, PP2), EGFR inhibitor (AG1478) and by inhibitors to extracellular matrix metalloproteinases (GM6001). Our data outline a mechanism how injury-induced endothelins may modulate the Müller cell responses by transactivation of EGFRs. The data give support to a view in which endothelins, among several other functions, serve as an injury-signal that regulate the gliotic response of Müller cells.
AG1478, endothelin receptor B agonist IRL1620, ERK1/2, gliosis, matrix-metalloproteinases, MAPK, N-methyl-D-aspartate, excitotoxic retinal injury, Src-kinase
Research subject Medical Science
IdentifiersURN: urn:nbn:se:uu:diva-281586OAI: oai:DiVA.org:uu-281586DiVA: diva2:914644