Cargando…

Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels

Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage-regulated gates, termed “activation” and “inactivation,” located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating o...

Descripción completa

Detalles Bibliográficos
Autores principales: Perry, Matthew D., Wong, Sophia, Ng, Chai Ann, Vandenberg, Jamie I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753607/
https://www.ncbi.nlm.nih.gov/pubmed/23980196
http://dx.doi.org/10.1085/jgp.201310975
_version_ 1782281863811825664
author Perry, Matthew D.
Wong, Sophia
Ng, Chai Ann
Vandenberg, Jamie I.
author_facet Perry, Matthew D.
Wong, Sophia
Ng, Chai Ann
Vandenberg, Jamie I.
author_sort Perry, Matthew D.
collection PubMed
description Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage-regulated gates, termed “activation” and “inactivation,” located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating occurs much more rapidly, and over a distinct range of voltages, compared with activation gating. Although it is clear that the fourth transmembrane segments (S4), within each subunit of the tetrameric channel, are important for controlling the opening and closing of the activation gate, their role during inactivation gating is much less clear. Here, we use rate equilibrium free energy relationship (REFER) analysis to probe the contribution of the S4 “voltage-sensor” helix during inactivation of Kv11.1 channels. Contrary to the important role that charged residues play during activation gating, it is the hydrophobic residues (Leu529, Leu530, Leu532, and Val535) that are the key molecular determinants of inactivation gating. Within the context of an interconnected multi-domain model of Kv11.1 inactivation gating, our REFER analysis indicates that the S4 helix and the S4–S5 linker undergo a conformational rearrangement shortly after that of the S5 helix and S5P linker, but before the S6 helix. Combining REFER analysis with double mutant cycle analysis, we provide evidence for a hydrophobic interaction between residues on the S4 and S5 helices. Based on a Kv11.1 channel homology model, we propose that this hydrophobic interaction forms the basis of an intersubunit coupling between the voltage sensor and pore domain that is an important mediator of inactivation gating.
format Online
Article
Text
id pubmed-3753607
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-37536072014-03-01 Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels Perry, Matthew D. Wong, Sophia Ng, Chai Ann Vandenberg, Jamie I. J Gen Physiol Research Articles Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage-regulated gates, termed “activation” and “inactivation,” located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating occurs much more rapidly, and over a distinct range of voltages, compared with activation gating. Although it is clear that the fourth transmembrane segments (S4), within each subunit of the tetrameric channel, are important for controlling the opening and closing of the activation gate, their role during inactivation gating is much less clear. Here, we use rate equilibrium free energy relationship (REFER) analysis to probe the contribution of the S4 “voltage-sensor” helix during inactivation of Kv11.1 channels. Contrary to the important role that charged residues play during activation gating, it is the hydrophobic residues (Leu529, Leu530, Leu532, and Val535) that are the key molecular determinants of inactivation gating. Within the context of an interconnected multi-domain model of Kv11.1 inactivation gating, our REFER analysis indicates that the S4 helix and the S4–S5 linker undergo a conformational rearrangement shortly after that of the S5 helix and S5P linker, but before the S6 helix. Combining REFER analysis with double mutant cycle analysis, we provide evidence for a hydrophobic interaction between residues on the S4 and S5 helices. Based on a Kv11.1 channel homology model, we propose that this hydrophobic interaction forms the basis of an intersubunit coupling between the voltage sensor and pore domain that is an important mediator of inactivation gating. The Rockefeller University Press 2013-09 /pmc/articles/PMC3753607/ /pubmed/23980196 http://dx.doi.org/10.1085/jgp.201310975 Text en © 2013 Perry et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Perry, Matthew D.
Wong, Sophia
Ng, Chai Ann
Vandenberg, Jamie I.
Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title_full Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title_fullStr Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title_full_unstemmed Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title_short Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels
title_sort hydrophobic interactions between the voltage sensor and pore mediate inactivation in kv11.1 channels
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753607/
https://www.ncbi.nlm.nih.gov/pubmed/23980196
http://dx.doi.org/10.1085/jgp.201310975
work_keys_str_mv AT perrymatthewd hydrophobicinteractionsbetweenthevoltagesensorandporemediateinactivationinkv111channels
AT wongsophia hydrophobicinteractionsbetweenthevoltagesensorandporemediateinactivationinkv111channels
AT ngchaiann hydrophobicinteractionsbetweenthevoltagesensorandporemediateinactivationinkv111channels
AT vandenbergjamiei hydrophobicinteractionsbetweenthevoltagesensorandporemediateinactivationinkv111channels