Publikationsserver der Universitätsbibliothek Marburg

Titel:Hämoxygenase-2 reguliert die Öffnungswahrscheinlichkeit des Kaliumkanals TREK-1durch die Produktion von Kohlenstoffmonoxid
Autor:Koschinsky, Kristin
Weitere Beteiligte: Preisig-Müller, Regina (PD Dr.)
Veröffentlicht:2015
URI:https://archiv.ub.uni-marburg.de/diss/z2015/0526
DOI: https://doi.org/10.17192/z2015.0526
URN: urn:nbn:de:hebis:04-z2015-05262
DDC:610 Medizin
Titel (trans.):Heme oxygenase 2 interacts with the potassium channel TREK-1 and modulates its open probability by producing carbon monoxide
Publikationsdatum:2016-04-14
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
heme oxygenase 2 (HO-2), Protein- Protein Interaktion, CO-freisetzende Moleküle (CORMs), Stickstoffmonoxid (NO), carbon monoxide (CO), TREK-1, protein-protein interaction, K2P-channel, Kohlenstoffmonoxid, K2P-Kanäle, nitric oxide (NO), CO-releasing molecules (CORMs), TREK-1, Hämoxygenase-2

Zusammenfassung:
Der mechanosensitive K2P-Kanal TREK-1 wird durch eine Vielzahl von physikalischen und chemischen Stimuli, sowie durch eine Reihe von Interaktionspartnern reguliert. Das Ziel dieser Arbeit bestand darin, die Interaktion des TREK-1 Kanals mit dem Enzym Hämoxygenase 2 (HO-2), welches den stereospezifischen Abbau von Häm zu Biliverdin, Fe2+ und CO katalysiert, zu charakterisieren und die funktionellen Auswirkungen aufzuklären. Die Interaktion zwischen dem Enzym HO-2 und TREK-1 konnte durch Koimmunopräzipitation bestätigt werden. Untersuchungen im Hefe-Zwei-Hybrid System mit HO-2 Verkürzungsmutanten zeigten, dass der distale Carboxyterminus der HO-2 eine wichtige Rolle bei der Interaktion mit dem TREK-1 Kanal spielt. Die funktionellen Auswirkungen der Interaktion wurden mittels Strommessungen in Xenopus Oozyten untersucht. Eine Koexpression von humaner HO-2 und TREK-1 führte zu einer signifikanten Erhöhung der Stromamplitude von TREK-1, während die Koexpression der katalytisch inaktiven Form des Enzyms HO-2H45N, die ebenfalls mit TREK-1 interagierte, keine signifikante Änderung der Stromamplitude im Kanal hervorrief. Die funktionelle Relevanz der katalytischen Aktivität der HO-2 wurde mit Hilfe von Aktivatoren und Inhibitoren untersucht. Zugabe von Hämin, einem Aktivator der HO-2, führte in Oozyten, die HO-2 konstitutiv exprimieren, zu einem signifikanten Anstieg des TREK-1 Stromes. Zusätzliche Koexpression der humanen HO-2 führte zu einer signifikant stärkeren Zunahme des TREK-1 Stromes. Applikation von Zinkprotoporphyrin (ZnPP), einem HO-2 Inhibitor, führte hingegen zu einer signifikanten Reduktion der TREK-1 Stromamplitude. Applikation von CO mit Hilfe des CO-freisetzenden Moleküls CORM-2 führte zu einer Aktivierung des TREK-1 Kanals in Xenopus Oozyten und HEK293 Zellen. Messungen mit PhotoCORM-S1 und CO-Gas zeigten ebenfalls eine signifikante Aktivierung des TREK-1 Kanals. Auch die mechanosensitiven K2P-Kanäle TREK-2 und TRAAK konnten in ähnlichem Ausmaß wie TREK-1 durch CO aktiviert werden. CO ist ein wichtiges zelluläres Signalmolekül, interagiert mit einer Vielzahl von Proteinen und kann eine Reihe von Signalwegen modulieren. Meine Untersuchungen zu möglichen CO-abhängigen Signalwegen zeigten, dass die verschiedenen Phosphorylierungsstellen S362 (PKG-abhängige Phosphorylierungsstelle) und S344 (PKA-abhängige Phosphorylierungsstelle) im Carboxyterminus des TREK-1 Kanals nicht an der CO-vermittelten Aktivierung beteiligt sind. Eine Deletion des zytosolisch lokalisierten TREK-1 Aminoterminus bzw. Carboxyterminus zeigte darüber hinaus, dass die verkürzten Kanalvarianten weiterhin durch CO aktiviert werden konnten. Die Aktivierung des TREK-1 Stromes durch das gasförmige Signalmolekül NO war bei der carboxyterminalen Verkürzungsvariante allerdings nicht mehr möglich. Diese Ergebnisse lassen vermuten, dass die gasförmigen Signalmoleküle CO und NO die Öffnungswahrscheinlichkeit von TREK-1 durch unterschiedliche Mechanismen beeinflussen. Eine direkte Wirkung von CO auf TREK-1 konnte durch inside-out Messungen in Giant-Patches von Xenopus Oozyten nachgewiesen werden. Meine Ergebnisse unterstützen die Hypothese, dass HO-2 an TREK-1 Kanäle bindet und durch lokale Produktion von CO die Öffungswahrscheinlichkeit des Kanals reguliert.

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