Yunping Song
Funktionale Eigenschaften von Ionenkanälen und Transportern tragen zu der synaptische Inhibition im zentralen Nervensystem von Säugern bei
Die inhibitorische Neurotransmission ist ein komplexes System aus unterschiedlichsten Kanälen und Transportern, die verschiedensten Regulationsmechanismen unterliegen. Aktivierung post-synaptischer ligandengesteuerter Ionenkanäle wie Glyzin- oder GABAA-Rezeptoren steuert die inhibitorische Neurotransmission direkt, während exzitatorische Aminosäuretransporter den inhibitorischen Effekt indirekt unterstützen, indem sie exzitatorische Neurotransmitter aus post- und extra-synaptischen Regionen beseitigen.
Für ein geregeltes Funktionieren des menschlichen Körpers sind die hier untersuchten Membranproteine unabdingbar.
1) In diesen Untersuchungen charakterisierten wir den Einfluss verschiedener Faktoren (Mutationen, extrazellulären pH und Neurosteroide) auf die Funktionen der exzitatorischen Aminosäuretransporter EAAT2 und EAAT4, als auch auf die inbitorischen, ligandengesteuerten Ionenkanäle Glyzin- und GABAA-Rezeptor.
Ladungsneutralisierung eines konservierten Aspartats in TM8 erzeugt profunde Änderungen in EAAT2 und EAAT4. Glutamat agiert als Inhibitor bei beiden Mutationen. Analysen der Kinetik bestätigten die verhinderte Interaktion von Na+-Ionen mit den leeren Transportern. Zusätzlich simulierten wir diesen Mechanismus mit einem etablierten Model für D486N EAAT2. Durch internes K+ wird die Mehrzahl der Transporter in den ´To´-Zustand versetzt, der eine sehr kleine Offenwahrscheinlichkeit aufweist; bei internem Na+ oder Glutamat werden WT als auch mutierte Transporter vornehmlich in den ´TiNa2´-Zustand versetzt. Die verminderte Öffnungsrate des ´TiNa2´-Zustands der mutierten Transporter ist verantwortlich für die beobachteten, kleineren Ströme unter diesen Bedingungen.
53
2) Extrazelluläre pH-Schwankungen verhindern glyzinerge Ströme. Die Tendenz einer beschleunigten Desensibilisierung des Stromes kann bei einer Verschiebung des pH´s um eine Einheit von dem neutralisierenden Wert beobachtet werden. Der Effekt wird durch weitere Ansäuerung verstärkt, d.h. eine signifikant schnellere Desensibilisierung kann beobachtet werden, ebenso wie eine signifikant verminderte relative Fläche-unter-Strom-Kurve und verminderten relativen Stromamplitude der stationären Phase. Heteromere 1Glyzinrezeptoren zeigen eine geringere pH-Empfindlichkeit verglichen mit den homodimeren Rezeptoren.
3) Die Neurosteroide Androsteron und Progesteron fungieren als allosterische Modulatoren für Glyzin und GABAA-Rezeptoren, wobei die Androsteron-Effekte auf GABAA-Rezeptoren stärker ausfallen, als die auf Glyzin-Rezeptoren. Androsteron (100 µM) kann GABAA-Rezeptoren sogar direkt aktivieren. Progesteron (100 µM) induziert eine leichte Antwort der α1 Glyzin- und α1GABAA-Rezeptoren.
Signifikant verstärkende Effekte von Androsteron und Progesteron auf GABAA- und Glyzin-Rezeptoren konnten beobachtet werden. Biphasische Dosis-Wirkungs-Beziehung deutet auf zwei unterschiedliche Bindestellen für diese Neurosteroide hin.
54
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