Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6

Voltage-gated ion channels possess charged domains that move in response to changes in transmembrane voltage. How this movement is transduced into gating of the channel pore is largely unknown. Here we show directly that two functionally important regions of the spHCN1 pacemaker channel, the S4–S5 l...

Descripción completa

Detalles Bibliográficos
Autores principales: Prole, David L., Yellen, Gary
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151568/
https://www.ncbi.nlm.nih.gov/pubmed/16908727
http://dx.doi.org/10.1085/jgp.200609590
_version_ 1782144744230486016
author Prole, David L.
Yellen, Gary
author_facet Prole, David L.
Yellen, Gary
author_sort Prole, David L.
collection PubMed
description Voltage-gated ion channels possess charged domains that move in response to changes in transmembrane voltage. How this movement is transduced into gating of the channel pore is largely unknown. Here we show directly that two functionally important regions of the spHCN1 pacemaker channel, the S4–S5 linker and the C-linker, come into close proximity during gating. Cross-linking these regions with high-affinity metal bridges or disulfide bridges dramatically alters channel gating in the absence of cAMP; after modification the polarity of voltage dependence is reversed. Instead of being closed at positive voltage and activating with hyperpolarization, modified channels are closed at negative voltage and activate with depolarization. Mechanistically, this reversal of voltage dependence occurs as a result of selectively eliminating channel deactivation, while retaining an existing inactivation process. Bridging also alters channel activation by cAMP, showing that interaction of these two regions can also affect the efficacy of physiological ligands.
format Text
id pubmed-2151568
institution National Center for Biotechnology Information
language English
publishDate 2006
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-21515682008-01-17 Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6 Prole, David L. Yellen, Gary J Gen Physiol Articles Voltage-gated ion channels possess charged domains that move in response to changes in transmembrane voltage. How this movement is transduced into gating of the channel pore is largely unknown. Here we show directly that two functionally important regions of the spHCN1 pacemaker channel, the S4–S5 linker and the C-linker, come into close proximity during gating. Cross-linking these regions with high-affinity metal bridges or disulfide bridges dramatically alters channel gating in the absence of cAMP; after modification the polarity of voltage dependence is reversed. Instead of being closed at positive voltage and activating with hyperpolarization, modified channels are closed at negative voltage and activate with depolarization. Mechanistically, this reversal of voltage dependence occurs as a result of selectively eliminating channel deactivation, while retaining an existing inactivation process. Bridging also alters channel activation by cAMP, showing that interaction of these two regions can also affect the efficacy of physiological ligands. The Rockefeller University Press 2006-09 /pmc/articles/PMC2151568/ /pubmed/16908727 http://dx.doi.org/10.1085/jgp.200609590 Text en Copyright © 2006, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Articles
Prole, David L.
Yellen, Gary
Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title_full Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title_fullStr Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title_full_unstemmed Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title_short Reversal of HCN Channel Voltage Dependence via Bridging of the S4–S5 Linker and Post-S6
title_sort reversal of hcn channel voltage dependence via bridging of the s4–s5 linker and post-s6
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2151568/
https://www.ncbi.nlm.nih.gov/pubmed/16908727
http://dx.doi.org/10.1085/jgp.200609590
work_keys_str_mv AT proledavidl reversalofhcnchannelvoltagedependenceviabridgingofthes4s5linkerandposts6
AT yellengary reversalofhcnchannelvoltagedependenceviabridgingofthes4s5linkerandposts6