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Titel:VAP-Proteine sind wesentliche Bestandteile nativer HCN2-Kanalkomplexe und regulieren die Funktion deskardialen If -Schrittmacherstroms
Autor:Silbernagel, Nicole
Weitere Beteiligte: Decher, Niels (Prof. Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0570
URN: urn:nbn:de:hebis:04-z2016-05705
DOI: https://doi.org/10.17192/z2016.0570
DDC: Naturwissenschaften
Titel (trans.):VAP proteins are essential components of native HCN2 channel complexes and are regulating the function of the cardiac If pacemaker current
Publikationsdatum:2017-09-14
Lizenz:https://rightsstatements.org/vocab/InC/1.0/

Dokument

Schlagwörter:
Bradykardie, VAP-Proteine, HCN, VAP proteins, bradycardia, HCN-Kanal, Ionenkanal, patch clamp, ion channel, Patch Clamp

Zusammenfassung:
HCN-Kanäle erfüllen die Schrittmacherfunktion in erregbaren Zellen des Herzmuskelgewebes und in vielen Neuronen des zentralen Nervensystems. Sie kontrollieren die Feuerrate der Neurone und somit die Frequenz der Aktionspotentiale.Sie haben die Eigenschaft während einer Hyperpolarisation der Membran zu aktivieren und so diese zu depolarisieren. In dieser Arbeit konnte gezeigt werden, dass das VAPB-Protein ein endogener Interaktionspartner des HCN2-Kanals ist und einen modulatorischen Effekt auf die Herzfrequenz, sowie die neuronale Distribution hat. Das VAPB-Protein hat einen zeitunabhängigen, jedoch konzentrationsabhängigen Einfluss auf die Stromamplitude. Das Öffnungsverhalten, sowie die Aktivierungskinetik bleiben hierbei unbeeinflusst. Zusammengefasst sprechen die Ergebnisse dieser Arbeit dafür, dass das VAPB-Protein einen „Trafficking“-Effekt auf das HCN2-Protein hat, das heißt einen Einfluss auf dessen zytosolischen Transport an die Membran. „Patch-Clamp“-Experimente der spontan aktiven Herzmuskelzelllinie HL-1 zeigten unter „Knock-Down“ Bedingungen mittels shVAPB eine verlängerte diastolische Depolarisation mit der Folge einer gesteigerten Aktionspotentialbreite (APD50). In vivo Experimente mit VAPB-„Knock-Out“-Mäusen bestätigten den Einfluss des VAPB-Proteins auf die Herzfrequenz.

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