title: HCN3 contributes to the ventricular action potential waveform in the murine heart.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Center for Integrated Protein Science CIPS-M, Department Pharmazie, Ludwig-Maximilians-Universität München, München, Germany.
authors: Stefanie
authors: S
authors: Fenske
authors: Robert
authors: R
authors: Mader
authors: Andreas
authors: A
authors: Scharr
authors: Christos
authors: C
authors: Paparizos
authors: Xiaochun
authors: X
authors: Cao-Ehlker
authors: Stylianos
authors: S
authors: Michalakis
authors: Lior
authors: L
authors: Shaltiel
authors: Martha
authors: M
authors: Weidinger
authors: Juliane
authors: J
authors: Stieber
authors: Susanne
authors: S
authors: Feil
authors: Robert
authors: R
authors: Feil
authors: Franz
authors: F
authors: Hofmann
authors: Christian
authors: C
authors: Wahl-Schott
authors: Martin
authors: M
authors: Biel
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004562:Electrocardiography; D006339:Heart Rate / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000502:physiology; D015221:Potassium Channels; D012849:Sinoatrial Node / Q000502:physiology; D016276:Ventricular Function / Q000502:physiology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578669:HCN3 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels