Hysteresis in the voltage dependence of HCN channels: Conversion between two modes affects pacemaker properties

Roope Männikkö, Shilpi Pandey, Hans P Larsson, Fredrik Elinder

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (τ ≈ 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.

Original languageEnglish
Pages (from-to)305-326
Number of pages22
JournalJournal of General Physiology
Volume125
Issue number3
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Molecular Conformation
Computer Simulation
Cardiac Arrhythmias

Keywords

  • Arrhythmia
  • HCN channel
  • Oocyte
  • Voltage clamp
  • Voltage shift

ASJC Scopus subject areas

  • Physiology

Cite this

Hysteresis in the voltage dependence of HCN channels : Conversion between two modes affects pacemaker properties. / Männikkö, Roope; Pandey, Shilpi; Larsson, Hans P; Elinder, Fredrik.

In: Journal of General Physiology, Vol. 125, No. 3, 01.03.2005, p. 305-326.

Research output: Contribution to journalArticle

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