Publikationsserver der Universitätsbibliothek Marburg

Titel:Die Rolle der L-Typ-Kalziumkanäle für die Schrittmacherfunktion in Locus coeruleus Neuronen der Maus
Autor:Schieber, Simon
Weitere Beteiligte: Decher, Niels (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0443
URN: urn:nbn:de:hebis:04-z2013-04434
DOI: https://doi.org/10.17192/z2013.0443
DDC: Medizin
Titel (trans.):The role of l-type calcium-channels for the pacemaker mechanism in Locus coeroleus neurons in mice
Publikationsdatum:2013-08-13
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Locus coeruleus, Dihydropyridine, calcium channels, pacemaker mechanism, dihydropyridines, spannungsabhängige Kalziumkanäle, Schrittmachermechanismus, Parkinsons disease, Parkinson-Krankheit, Locus coeruleus, Elektrophysiologie

Zusammenfassung:
Der Locus coeruleus (LC) ist aufgrund seiner bedeutenden Rolle in der Entstehung der Parkinson-Krankheit von großem wissenschaftlichen und therapeutischen Interesse. Im Verlauf der Erkrankung gehen dopaminerge Neurone der Substantia nigra pars compacta (SNpc) aus bisher ungeklärten Ursachen zugrunde. Noch bevor die SNpc betroffen ist, sind bereits degenerative Prozesse im Locus coeruleus nachweisbar. Die noradrenergen Neurone des LC haben protektiven Einfluss auf das Überleben der Substantia nigra und sind aus diesem Grund wichtiger Bestandteil der Forschung zur Parkinson-Krankheit. Die Neurone des LC sind autonome Schrittmacherzellen. Der Mechanismus, der dieser Schrittmacheraktivität zugrunde liegt, ist bislang weitgehend ungeklärt. Ziel dieser Arbeit ist es, diesen Mechanismus genauer zu untersuchen und vor allem die Rolle der L-Typ-Kalziumkanäle zu klären. Hierfür wurden elektrophysiologische, molekularbiologische und fluoreszenzmikroskopische Experimente an Hirnschnitten von Wildtyp-Mäusen (C57Bl/6) durchgeführt. Mit der Patch-Clamp Technik gemessene Einzelzellableitungen haben ergeben, dass die alleinige Gabe des Kalziumantagonisten Isradipin keinen Einfluss auf das Entladungsmuster der LC-Neurone hat. Die Vermutung, die kontinuierlich generierten Aktionspotentiale beruhen auf regelmäßigen depolarisierenden Kalziumströmen, kann damit überraschenderweise widerlegt werden. Dennoch sind L-Typ-Kalziumkanäle in diesen Zellen aktiv: Nach Blockade der Aktionspotentiale durch Tetrodotoxin sind -- ähnlich wie in SNpc-Neuronen -- auch in Zellen des LC langsame Membranoszillationen ("slow oscillatory potentials"') erkennbar, die durch Isradipin effektiv blockiert werden können. Kalziumströme sind demnach an der elektrischen Aktivität der LC-Neurone beteiligt, für die autonome Generierung von Aktionspotentialen aber nicht essentiell. Ein mögliches Modell zur Erklärung der erhöhten Vulnerabilität von SNpc- und LC-Neuronen bei der Parkinson-Krankheit macht durch intrazelluläres Kalzium verursachten oxidativen Stress für das verfrühte Zellsterben verantwortlich. Durch die Blockade der L-Typ-Kalziumkanäle in LC-Neuronen kann demnach entlastend auf den Kalziumhaushalt der Zellen Einfluss genommen werden, ohne die Funktion des Locus coeruleus grundsätzlich zu beeinträchtigen. Dieser Umstand macht den LC zu einem potentiell interessanten Wirkungsort für neue neuroprotektive Therapieansätze.

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