Kinetic relationship between the voltage sensor and the activation gate in spHCN channels

The Journal of General Physiology
Andrew Bruening-WrightH Peter Larsson


Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are activated by membrane hyperpolarizations that cause an inward movement of the positive charges in the fourth transmembrane domain (S4), which triggers channel opening. The mechanism of how the motion of S4 charges triggers channel opening is unknown. Here, we used voltage clamp fluorometry (VCF) to detect S4 conformational changes and to correlate these to the different activation steps in spHCN channels. We show that S4 undergoes two distinct conformational changes during voltage activation. Analysis of the fluorescence signals suggests that the N-terminal region of S4 undergoes conformational changes during a previously characterized mode shift in HCN channel voltage dependence, while a more C-terminal region undergoes an additional conformational change during gating charge movements. We fit our fluorescence and ionic current data to a previously proposed 10-state allosteric model for HCN channels. Our results are not compatible with a fast S4 motion and rate-limiting channel opening. Instead, our data and modeling suggest that spHCN channels open after only two S4s have moved and that S4 motion is rate limiting during voltage activation of spHCN channels.


Mar 1, 1984·The Journal of Physiology·D DiFrancesco
Apr 1, 1995·Pflügers Archiv : European journal of physiology·W M WeberW Clauss
Jan 1, 1993·Annual Review of Physiology·D DiFrancesco
Feb 1, 1994·The Journal of General Physiology·W N ZagottaR W Aldrich
Feb 1, 1994·The Journal of General Physiology·W N ZagottaR W Aldrich
Dec 1, 1995·The Journal of Membrane Biology·W M WeberW Clauss
Jul 1, 1997·Cellular and Molecular Life Sciences : CMLS·E CentinaioA Peres
Mar 7, 1998·The Journal of General Physiology·N E Schoppa, F J Sigworth
Mar 7, 1998·The Journal of General Physiology·N E Schoppa, F J Sigworth
May 31, 2001·The Journal of General Physiology·C AltomareD DiFrancesco
Jan 7, 2003·The EMBO Journal·Andreas LudwigFranz Hofmann
Mar 18, 2003·Nature Neuroscience·Federico SestiSteve A N Goldstein
May 17, 2003·The Journal of Clinical Investigation·Eric Schulze-BahrDirk Isbrandt
Dec 17, 2003·The Journal of General Physiology·Sriharsha VemanaH Peter Larsson
Mar 6, 2004·Proceedings of the National Academy of Sciences of the United States of America·H Peter LarssonMichael P Kavanaugh
Feb 16, 2005·The Journal of General Physiology·Roope MännikköFredrik Elinder
Jan 12, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Andrew Bruening-Wright, H Peter Larsson

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