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The Endothelin B Receptor Transactivates Epidermal Growth Factor Receptors in primary chicken Müller cells and in MIO-M1 Human Müller Cells
Uppsala University. (Finn Hallböök group)ORCID iD: Save personal data »
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
AG1478, endothelin receptor B agonist IRL1620, ERK1/2, gliosis, matrix-metalloproteinases, MAPK, N-methyl-D-aspartate, excitotoxic retinal injury, Src-kinase
National Category
Neurosciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-281586OAI: oai:DiVA.org:uu-281586DiVA: diva2:914644
Available from: 2016-03-24 Created: 2016-03-24 Last updated: 2016-05-12
In thesis
1. Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina: Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems
Open this publication in new window or tab >>Modulation of the Progenitor Cell and Homeostatic Capacities of Müller Glia Cells in Retina: Focus on α2-Adrenergic and Endothelin Receptor Signaling Systems
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Müller cells are major glial cells in the retina and have a broad range of functions that are vital for the retinal neurons. During retinal injury gliotic response either leads to Müller cell dedifferentiation and formation of a retinal progenitor or to maintenance of mature Müller cell functions. The overall aim of this thesis was to investigate the intra- and extracellular signaling of Müller cells, to understand how Müller cells communicate during an injury and how their properties can be regulated after injury. Focus has been on the α2-adrenergic receptor (α2-ADR) and endothelin receptor (EDNR)-induced modulation of Müller cell-properties after injury.

The results show that α2-ADR stimulation by brimonidine (BMD) triggers Src-kinase mediated ligand-dependent and ligand-independent transactivation of epidermal growth factor receptor (EGFR) in both chicken and human Müller cells. The effects of this transactivation in injured retina attenuate injury-induced activation and dedifferentiation of Müller cells by attenuating injury-induced ERK signaling. The attenuation was concomitant with a synergistic up-regulation of negative ERK- and RTK-feedback regulators during injury. The data suggest that adrenergic stress-signals modulate glial responses during retinal injury and that α2-ADR pharmacology can be used to modulate glial injury-response. We studied the effects of this attenuation of Müller cell dedifferentiation on injured retina from the perspective of neuroprotection. We analyzed retinal ganglion cell (RGC) survival after α2-ADR stimulation of excitotoxically injured chicken retina and our results show that α2-ADR stimulation protects RGCs against the excitotoxic injury. We propose that α2-ADR-induced protection of RGCs in injured retina is due to enhancing the attenuation of the glial injury response and to sustaining mature glial functions. Moreover, we studied endothelin-induced intracellular signaling in Müller cells and our results show that stimulation of EDNRB transactivates EGFR in Müller cells in a similar way as seen after α2-ADR stimulation. These results outline a mechanism of how injury-induced endothelins may modulate the gliotic responses of Müller cells.

The results obtained in this thesis are pivotal and provide new insights into glial functions, thereby uncovering possibilities to target Müller cells by designing neuroprotective treatments of retinal degenerative diseases or acute retinal injury.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1201
Keyword
Alpha2-adrenergic receptor, Brimonidine, Brn3a, Dedifferentiation, Endothelin, EGFR, ERK1/2, Neuroprotection, NMDA, MIO-M1 human Müller cell, Müller cells, Retina, Retinal ganglion cells, Src-kinase, Transactivation.
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-281569 (URN)978-91-554-9527-5 (ISBN)
Public defence
2016-05-19, B21, BMC, Husagatan 03, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-04-28 Created: 2016-03-24 Last updated: 2016-05-12

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Harun-Or-Rashid, Mohammad

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