RATIONALE: The hyperpolarization-activated current I(h) that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether I(h) is also relevant for normal function of cardiac ventricles. OBJECTIVE: To study the role of the HCN3-mediated component of ventricular I(h) in normal ventricular function. METHODS AND RESULTS: To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficient mouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials in HCN3-deficient mice. Cardiomyocytes of HCN3-deficient mice displayed approximately 30% reduction of total I(h). At physiological ionic conditions, the HCN3-mediated current had a reversal potential of approximately -35 mV and displayed ultraslow deactivation kinetics. CONCLUSIONS: We propose that HCN3 together with other members of the HCN channel family confer a depolarizing background current that regulates ventricular resting potential and counteracts the action of hyperpolarizing potassium currents in late repolarization. In conclusion, our data indicate that HCN3 plays an important role in shaping the cardiac action potential waveform.
RATIONALE: The hyperpolarization-activated current I(h) that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether I(h) is also relevant for normal function of cardiac ventricles. OBJECTIVE: To study the role of the HCN3-mediated component of ventricular I(h) in normal ventricular function. METHODS AND RESULTS: To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficientmouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials in HCN3-deficientmice. Cardiomyocytes of HCN3-deficientmice displayed approximately 30% reduction of total I(h). At physiological ionic conditions, the HCN3-mediated current had a reversal potential of approximately -35 mV and displayed ultraslow deactivation kinetics. CONCLUSIONS: We propose that HCN3 together with other members of the HCN channel family confer a depolarizing background current that regulates ventricular resting potential and counteracts the action of hyperpolarizing potassium currents in late repolarization. In conclusion, our data indicate that HCN3 plays an important role in shaping the cardiac action potential waveform.
Authors: Eric D Larson; Joshua R St Clair; Whitney A Sumner; Roger A Bannister; Cathy Proenza Journal: Proc Natl Acad Sci U S A Date: 2013-10-15 Impact factor: 11.205
Authors: Verena Hammelmann; Marc Sebastian Stieglitz; Henrik Hülle; Karim Le Meur; Jennifer Kass; Manuela Brümmer; Christian Gruner; René Dominik Rötzer; Stefanie Fenske; Jana Hartmann; Benedikt Zott; Anita Lüthi; Saskia Spahn; Markus Moser; Dirk Isbrandt; Andreas Ludwig; Arthur Konnerth; Christian Wahl-Schott; Martin Biel Journal: JCI Insight Date: 2019-05-02
Authors: Ning Li; Thomas A Csepe; Brian J Hansen; Halina Dobrzynski; Robert S D Higgins; Ahmet Kilic; Peter J Mohler; Paul M L Janssen; Michael R Rosen; Brandon J Biesiadecki; Vadim V Fedorov Journal: Circ Arrhythm Electrophysiol Date: 2015-08-24