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

The Journal of General Physiology
Andrew Bruening-WrightH Peter Larsson

Abstract

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.

References

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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Citations

Dec 22, 2009·Nature Structural & Molecular Biology·Carlos GonzalezH Peter Larsson
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Nadine L WicksEdgar C Young
Feb 14, 2008·The Journal of General Physiology·Alex K Lyashchenko, Gareth R Tibbs
Jul 16, 2008·The Journal of General Physiology·Moninder VaidDavid Fedida
Nov 17, 2010·The Journal of General Physiology·Antonios PantazisRiccardo Olcese
Apr 27, 2011·The Journal of General Physiology·Georges A Haddad, Rikard Blunck
Oct 17, 2012·The Journal of General Physiology·Sujung Ryu, Gary Yellen
Feb 13, 2013·The Journal of General Physiology·Carlos GonzalezH Peter Larsson
Oct 17, 2012·The Journal of General Physiology·Matthew C Trudeau
May 29, 2008·Clinical and Experimental Pharmacology & Physiology·Stephan A Pless, Joseph W Lynch
Jun 27, 2008·American Journal of Physiology. Cell Physiology·Sriharsha VemanaH Peter Larsson
Apr 16, 2014·The Journal of General Physiology·Weihua GaoLei Zhou
Dec 20, 2011·Nature Chemical Biology·Jana KuschKlaus Benndorf
Sep 11, 2014·Journal of Molecular Biology·Prakash Subramanyam, Henry M Colecraft
Dec 5, 2015·Biophysical Journal·Susanne ThonKlaus Benndorf
Jul 1, 2015·The Journal of Membrane Biology·Kaylee E A MageeEdgar C Young
Oct 8, 2013·Biophysical Journal·S ThonK Benndorf
Jun 28, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hans P KochH Peter Larsson
Mar 23, 2018·PLoS Computational Biology·Sabine HummertKlaus Benndorf
May 23, 2012·Nature Materials·Themistoklis ProdromakisLeon Chua
Jul 9, 2009·Physiological Reviews·Martin BielXiangang Zong
May 3, 2013·Physiology·T HoshiR Olcese
Jul 10, 2019·Nature Structural & Molecular Biology·Gucan DaiWilliam N Zagotta
Aug 23, 2019·The Journal of General Physiology·John Cowgill, Baron Chanda
Dec 14, 2018·The Journal of General Physiology·Vinay IdikudaLei Zhou
Jul 1, 2018·The Journal of General Physiology·Mallikarjuna Rao SunkaraKlaus Benndorf
Jul 9, 2020·Frontiers in Pharmacology·Carlos A Villalba-Galea
Mar 19, 2020·Nature Communications·Rosamary RamentolH Peter Larsson
Jul 27, 2021·Progress in Biophysics and Molecular Biology·Delbert Yip, Eric Accili
Sep 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xiaoan WuH Peter Larsson

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Methods Mentioned

BETA
Fluorescence

Software Mentioned

pClamp

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