Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Cav- und KCa/SK- Ionenkanalfamilien in Locus Coeruleus Neuronen der Maus - Funktionelle Charakterisierung und Implikationen für die Parkinson-Erkrankung
Autor:Matschke, Lina
Weitere Beteiligte: Decher, Niels (Prof. Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0458
DOI: https://doi.org/10.17192/z2016.0458
URN: urn:nbn:de:hebis:04-z2016-04585
DDC: Naturwissenschaften
Titel (trans.):The Cav- und KCa/SK- ion channel families in Locus Coeruleus neurons of the mouse - Functional characterization and implications for Parkinson’s disease
Publikationsdatum:2017-02-03
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
calciumaktivierter Kaliumkanal, calcium activated potassium channel, Calciumkanal, calcium channel, Patch Clamp, Locus coeruleus, Parkinson-Krankheit, Kaliumkanal, Locus Coeruleus, Parkinson´s disease

Zusammenfassung:
Der Locus Coeruleus (LC) ist ein noradrenerger Kern des Hirnstammes, der an der Regulation vielfältiger, physiologischer Prozesse beteiligt ist. Störungen des LC-Noradrenalin Systems sind in der Pathogenese verschiedener psychiatrischer und neurodegenerativer Erkrankungen beteiligt und sind ein frühes Kennzeichen der Parkinson-Krankheit (PD). Während die Degeneration von Neuronen der Substantia Nigra pars compacta (SNpc) den motorischen Leitsymptomen der PD unterliegt, wird der ausgeprägte Verlust noradrenerger Neurone des LC für einen Großteil der nichtmotorischen Dysfunktionen dieser Erkrankung verantwortlich gemacht. Die Ursachen für die selektive Vulnerabilität der LC Neurone in der Pathogenese der PD sind bislang jedoch weitestgehend unklar. Um eine tonische Noradrenalin-Ausschüttung zu gewährleisten, verfügen LC Neurone über einen intrinsischen Schrittmachermechanismus, welcher direkt an intrazelluläre Überlebenssignalwege gekoppelt ist. So führt aktivitätsabhängiger, durch L-Typ Ca2+ Kanäle vermittelter Ca2+ Influx, zu oxidativem Stress in LC Neuronen und anderen von der PD Pathogenese betroffenen Kerngebieten. Des Weiteren wird eine neuroprotektive Rolle Ca2+ aktivierter Kaliumkanäle postuliert, welche den Schrittmachermechanismus dopaminerger SNpc Neurone modulieren. Die Identifikation von Ionenkanälen, die der elektrischen Aktivität unterliegen, kann somit zu einem besseren Verständnis der selektiven Vulnerabilität coerulärer Neurone führen. Innerhalb dieser Arbeit wurden daher mittels RT-PCR Expressionsanalysen und Patch-Clamp Messungen in akuten Hirnstammschnitten die molekulare Komposition und Funktion verschiedener Ionenkanalfamilien in LC Neuronen der Maus charakterisiert. Zunächst erstellte ich ein Profil bezüglich der elektrophysiologischen Charakteristika und der Expression kaliumselektiver Ionenkanäle coerulärer Neurone. Diese Analysen zeigten, dass der elektrophysiologische Phänotyp der LC Neurone durch regelmäßige, breite Aktionspotenziale mit einer ausgeprägten Nachhyperpolarisation, die um ein depolarisiertes Membranpotenzial fluktuieren, gekennzeichnet ist. Mittels der Expressionsanalyse konnte ich die molekulare Komposition spannungsabhängiger Kaliumkanäle aufklären, die wahrscheinlich den A-Typ K+ Strom und den persistierenden K+ Strom der LC Neurone vermitteln. Als A-Typ Kaliumkanäle wurden unter anderem Kv4.3 sowie Kv1 in Kombination mit Kvβ1 detektiert, welche durch das oxidative Potenzial der Zelle reguliert werden und deshalb unter pathologischen Bedingungen mit gestörter Funktion der Mitochondrien von Bedeutung sein könnten. Des Weiteren detektierte ich Amplifikate der GIRK Kanal Unterheinheiten GIRK-1 und GIRK-4 sowie verschiedene K2P Kanal-Untereinheiten, welche an der Aufrechterhaltung des Ruhemembranpotenzials zentraler Neurone beteiligt sind. Zur funktionellen Charakterisierung spannungsabhängiger Ca2+ Kanäle führte ich RT-PCR Expressionsanalysen sowie Patch-Clamp Messungen in Kombination mit L- und T-Typ Ca2+ Kanal Blockern durch. Diese Experimente zeigten, dass sowohl Ca2+ Kanäle der Unterfamilien Cav1 als auch Cav3 in LC Neuronen exprimiert sind und eine ausgeprägte „low voltage“ aktivierte Ca2+ Leitfähigkeit vermitteln. Die Analyse der Aktionspotenzial-Folgen ergab, dass weder die Inhibition von L- noch von T-Typ Ca2+ Kanälen allein die Feurrate oder die Aktionspotenzial-Parameter der LC Neurone verändert. Die kombinierte Applikation der Kanal-Blocker führte jedoch zu einer signifikanten Reduktion der Nachhyperpolarisation und daraus resultierend zu einer Beschleunigung der Feuerrate. Diese Ergebnisse beschreiben erstmals die funktionelle Expression von T-Typ Ca2+ Kanälen in LC Neuronen und demonstrieren ihre Rolle bei der Modulation des Schrittmachermechanismus im Zusammenspiel mit L-Typ Ca2+ Kanälen. T-Typ Ca2+ Kanäle sollten demnach neben den „low-voltage“ aktivierten L-Typ Ca2+ Kanälen als Kandidaten in Betracht gezogen werden, die aktivitätsabhängigen oxidativen Stress im Kontext pathologischer Bedingungen vermitteln könnten. Im Rahmen der funktionellen Charakterisierung Ca2+ aktivierter Kaliumkanäle detektierte ich die Expression der SK Kanal Familienmitglieder SK1, SK2 und SK3 in LC Neuronen. Mittels Patch-Clamp Messungen in Kombination mit dem selektiven SK Kanal Blocker Apamin und dem positiven SK Kanal Modulator NS309 konnte ich demonstrieren, dass SK Kanäle maßgeblich für die während der Nachhyperpolarisation fließenden K+ Auswärtsströme verantwortlich sind. Während Aufnahmen der Aktionspotenzialabfolgen bewirkte die Inhibition der SK Kanäle eine Reduktion der Nachhyperpolarisation und eine beschleunigte Feuerrate, während ihre Aktivierung zu einer Vergrößerung der Nachhyperpolarisation und einer verlangsamten Frequenz führte. SK Kanäle können demnach als wichtige Regulatoren der Schrittmacherfrequenz von LC Neuronen angesehen werden. Mittels Calcium Imaging Experimenten im in vitro Glutamat- und Rotenon-Toxizitätsmodell konnte ich darüber hinaus zeigen, dass die pharmakologische SK Kanal Aktivierung die Dysregulation der Ca2+ Homöostase unter toxischen Bedingungen verhindert. Mittels Patch-Clamp Messungen konnte ich erstmals demonstrieren, dass die akute Rotenon-Exposition eine Depolarisation und eine Steigerung der Aktionspotenzial-Frequenz in LC Neuronen induziert, welche durch die SK Kanal Aktivierung unterbunden werden konnte. Stereologische Analysen zeigten schließlich, dass die SK Kanal Aktivierung mit NS309 signifikant der Degeneration von LC Neuronen im in vitro Rotenon- Toxizitätsmodell entgegenwirkt. Die Aktivierung von SK Kanälen wird demnach als ein vielversprechender Ansatzpunkt zur Neuroprotektion des LC während früher Stadien der PD Pathogenese postuliert.

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