Kardiale Zwei-Porendomänen-Kaliumkanäle (K2P): Physiologie, Pharmakologie und therapeutisches Potenzial

Zusammenfassung

Unkontrollierte elektrische Aktivität an Biomembranen von Kardiomyozyten kann Herzrhythmusstörungen verursachen. Trotz einiger Fortschritte in den vergangenen Jahren basiert die medikamentöse antiarrhythmische Therapie weiterhin überwiegend auf unselektiven Mechanismen, die zu begrenzter Wirksamkeit und Unverträglichkeiten führen. Es besteht daher ein Bedarf an neuen, spezifischeren Konzepten zur Pharmakotherapie kardialer Arrhythmien. So genannte Zwei-Porendomänen-Kaliumkanäle (K2P) leiten Kalium-Hintergrundströme und sind für die Stabilisierung des Ruhemembranpotentials sowie für die Generierung des Herzaktionspotentials von Bedeutung. Klinisch etablierte Wirkstoffe wie Amiodaron, Carvedilol und Dronedaron hemmen neben ihren primären Zielstrukturen auch kardiale K2P Kanäle. Diese Kanalfamilie stellt daher einen möglichen Angriffspunkt für die Entwicklung zukünftiger antiarrhythmischer Substanzen dar. Der aktuelle Stand der Forschung zu Funktion, Regulation und kardialem Stellenwert der K2P Kanäle ist Gegenstand dieser Arbeit.

Abstract

Uncontrolled electrical activity caused by ion channel dysfunction produces arrhythmia in the heart. Despite recent advances in pharmaceutical research and development, effective and safe pharmacological management of cardiac arrhythmia still remains an unmet medical need. The emerging family of two-pore-domain potassium (K2P) channels stabilizes the resting membrane potential and facilitates action potential repolarization. In the heart, genetic inactivation or inhibition of two-pore-domain K + (K2P) currents by class III antiarrhythmic drugs results in action potential prolongation. In particular, human K2P3.1 channels are selectively expressed in the atria and represent targets for the pharmacological management of atrial fibrillation. Furthermore, stretch-sensitive K2P2.1 channels are implicated in mechanoelectrical feedback and arrhythmogenesis. The current knowledge on function, regulation, and cardiac significance of K2P channels is summarized in this work, and potential therapeutic implications are highlighted.

Schlüsselwörter

Zwei-Porendomänen- Kaliumkanäle (K2P) - Herzrhythmusstörungen - Vorhofflimmern - Antiarrhythmika - kardiales Aktionspotenzial

Keywords

two-pore-domain potassium (K2P) channels - cardiac arrhythmia - atrial fibrillation - antiarrhythmic drugs - cardiac action potential

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