title: Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels.
abstract: Hyperpolarization-activated, cyclic-nucleotide-gated (HCN) channels regulate pacemaker activity in the heart and the brain. Previously, we showed that spHCN and HCN1 channels undergo mode shifts in their voltage dependences, shifting the conductance versus voltage curves by more than +50 mV when measured from a hyperpolarized potential compared to a depolarized potential. In addition, the kinetics of the ionic currents changed in parallel to these voltage shifts. In the studies reported here, we tested whether slower cardiac HCN channels also display similar mode shifts. We found that HCN2 and HCN4 channels expressed in oocytes from the frog Xenopus laevis do not display the activation kinetic changes that we observed in spHCN and HCN1. However, HCN2 and HCN4 channels display changes in their tail currents, suggesting that these channels also undergo mode shifts and that the conformational changes underlying the mode shifts are due to conserved aspects of HCN channels. With computer modelling, we show that in channels with relatively slow opening kinetics and fast mode-shift transitions, such as HCN2 and HCN4 channels, the mode shift effects are not readily observable, except in the tail kinetics. Computer simulations of sino-atrial node action potentials suggest that the HCN2 channel, together with the HCN1 channel, are important regulators of the heart firing frequency and that the mode shift is an important property to prevent arrhythmic firing. We conclude that although all HCN channels appear to undergo mode shifts - and thus may serve to prevent arrhythmic firing - it is mainly observable in ionic currents from HCN channels with faster kinetics.
authors.affiliation: Department of Biomedicine and Surgery, Division of Cell Biology, Linköpings Universitet, SE-581 85 Linköping, Sweden. fredrik.elinder@ibk.liu.se
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
authors.forename: Roope
authors.initials: R
authors.lastname: Männikkö
authors.forename: Shilpi
authors.initials: S
authors.lastname: Pandey
authors.forename: H Peter
authors.initials: HP
authors.lastname: Larsson
mesh_terms: D000818:Animals; D003198:Computer Simulation; D000242:Cyclic AMP / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; C578710:HCN2 protein, human; C119587:HCN4 protein, human; C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D004247:DNA; D000242:Cyclic AMP