Dokument

Zusammenfassung:
Der Gardos-Kanal (KCa3.1) vermittelt den Ca2+-abhängigen Ausstrom von K+ und Cl- (den Gardos-Effekt) im Erythrozyten. Hierdurch kommt es zu einer Hyperpolarisation der Zellmembran und einem osmotisch bedingten Schrumpfen der Zelle. Diesem Ca2+-aktivierten K+-Kanal wird daher eine entscheidende Rolle für die physiologische Volumenregulation in zirkulierenden Erythrozyten, sowie auch für Krankheiten mit einer pathologischen Volumenregulation zugeschrieben. Insbesondere in der Pathogenese der Sichelzellanämie nimmt der Gardos-Kanal eine zentrale Stellung ein, wodurch diesem Kanal ein besonderes Interesse zuteil wird. Hochpotente, selektive Gardos-Kanal-Inhibitoren, wie beispielsweise Senicapoc, werden aktuell in der Therapie der Sichelzellanämie evaluiert. Während die pathophysiologische Bedeutsamkeit des Gardos-Kanals in der Sichelzellanämie und anderen Erkrankungen intensiv untersucht wurde, ist die tatsächliche funktionelle Relevanz von KCa3.1 sowohl für die physiologische Volumenregulation als auch für die Mechanismen der Eryptose (in Anlehnung an die Apoptose kernhaltiger Zellen) unklar. Auch wurden die Folgen einer genetischen Störung der Expression bis dato nicht detailliert untersucht. Die vorliegende Studie erlaubt die Einordung der physiologischen Rolle. Bei einer Störung der genetischen Expression von KCa3.1 in Mäusen entwickeln diese Tiere eine progressive, moderate Splenomegalie und eine milde Makrozytose. Die Erythrozyten dieser Knock-out Mäuse weisen eine erhöhte Fragilität bei hypoosmotischem Stress im Sinne einer gestörten Volumenregulation und eine verminderte Deformierbarkeit bei der Filtration durch kleine Poren auf. Diese funktionellen Defekte führen zu einer erhöhten Sequestration in der Milz, begleitet von einer erhöhten Eisenablagerung, die hierauf mit einer Arbeitshypertrophie in Form einer stetig zunehmenden Splenomegalie reagiert. Weiterhin konnte mit dieser Studie gezeigt werden, dass der Gardos-Kanal eine zentrale Stellung in der physiologischen Volumenregulation im Erythrozyten einnimmt, die bei einem Ausfall nicht durch andere Systeme kompensiert werden kann. Anders als von anderen Autoren postuliert, konnte keine maßgebliche Rolle von KCa3.1 für die Eryptose nachgewiesen werden. Dabei stellt die vorliegende Studie die erste in vivo Studie zu diesem Themenkomplex dar.

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